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Gangopadhyay K, Roy S, Sen Gupta S, Chandradasan A, Chowdhury S, Das R. Regulating the discriminatory response to antigen by T-cell receptor. Biosci Rep 2022; 42:BSR20212012. [PMID: 35260878 PMCID: PMC8965820 DOI: 10.1042/bsr20212012] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2022] [Revised: 03/04/2022] [Accepted: 03/08/2022] [Indexed: 11/17/2022] Open
Abstract
The cell-mediated immune response constitutes a robust host defense mechanism to eliminate pathogens and oncogenic cells. T cells play a central role in such a defense mechanism and creating memories to prevent any potential infection. T cell recognizes foreign antigen by its surface receptors when presented through antigen-presenting cells (APCs) and calibrates its cellular response by a network of intracellular signaling events. Activation of T-cell receptor (TCR) leads to changes in gene expression and metabolic networks regulating cell development, proliferation, and migration. TCR does not possess any catalytic activity, and the signaling initiates with the colocalization of several enzymes and scaffold proteins. Deregulation of T cell signaling is often linked to autoimmune disorders like severe combined immunodeficiency (SCID), rheumatoid arthritis, and multiple sclerosis. The TCR remarkably distinguishes the minor difference between self and non-self antigen through a kinetic proofreading mechanism. The output of TCR signaling is determined by the half-life of the receptor antigen complex and the time taken to recruit and activate the downstream enzymes. A longer half-life of a non-self antigen receptor complex could initiate downstream signaling by activating associated enzymes. Whereas, the short-lived, self-peptide receptor complex disassembles before the downstream enzymes are activated. Activation of TCR rewires the cellular metabolic response to aerobic glycolysis from oxidative phosphorylation. How does the early event in the TCR signaling cross-talk with the cellular metabolism is an open question. In this review, we have discussed the recent developments in understanding the regulation of TCR signaling, and then we reviewed the emerging role of metabolism in regulating T cell function.
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Affiliation(s)
- Kaustav Gangopadhyay
- Department of Biological Sciences, Indian Institute of Science Education and Research Kolkata, Mohanpur campus, Mohanpur 741246, India
| | - Swarnendu Roy
- Department of Biological Sciences, Indian Institute of Science Education and Research Kolkata, Mohanpur campus, Mohanpur 741246, India
| | - Soumee Sen Gupta
- Department of Biological Sciences, Indian Institute of Science Education and Research Kolkata, Mohanpur campus, Mohanpur 741246, India
| | - Athira C. Chandradasan
- Department of Biological Sciences, Indian Institute of Science Education and Research Kolkata, Mohanpur campus, Mohanpur 741246, India
| | - Subhankar Chowdhury
- Department of Biological Sciences, Indian Institute of Science Education and Research Kolkata, Mohanpur campus, Mohanpur 741246, India
| | - Rahul Das
- Department of Biological Sciences, Indian Institute of Science Education and Research Kolkata, Mohanpur campus, Mohanpur 741246, India
- Centre for Advanced Functional Materials, Indian Institute of Science Education and Research Kolkata, Mohanpur campus, Mohanpur 741246, India
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Meilleur CE, Memarnejadian A, Shivji AN, Benoit JM, Tuffs SW, Mele TS, Singh B, Dikeakos JD, Topham DJ, Mu HH, Bennink JR, McCormick JK, Haeryfar SMM. Discordant rearrangement of primary and anamnestic CD8+ T cell responses to influenza A viral epitopes upon exposure to bacterial superantigens: Implications for prophylactic vaccination, heterosubtypic immunity and superinfections. PLoS Pathog 2020; 16:e1008393. [PMID: 32433711 PMCID: PMC7239382 DOI: 10.1371/journal.ppat.1008393] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2019] [Accepted: 02/10/2020] [Indexed: 12/21/2022] Open
Abstract
Infection with (SAg)-producing bacteria may precede or follow infection with or vaccination against influenza A viruses (IAVs). However, how SAgs alter the breadth of IAV-specific CD8+ T cell (TCD8) responses is unknown. Moreover, whether recall responses mediating heterosubtypic immunity to IAVs are manipulated by SAgs remains unexplored. We employed wild-type (WT) and mutant bacterial SAgs, SAg-sufficient/deficient Staphylococcus aureus strains, and WT, mouse-adapted and reassortant IAV strains in multiple in vivo settings to address the above questions. Contrary to the popular view that SAgs delete or anergize T cells, systemic administration of staphylococcal enterotoxin B (SEB) or Mycoplasma arthritidis mitogen before intraperitoneal IAV immunization enlarged the clonal size of ‘select’ IAV-specific TCD8 and reshuffled the hierarchical pattern of primary TCD8 responses. This was mechanistically linked to the TCR Vβ makeup of the impacted clones rather than their immunodominance status. Importantly, SAg-expanded TCD8 retained their IFN-γ production and cognate cytolytic capacities. The enhancing effect of SEB on immunodominant TCD8 was also evident in primary responses to vaccination with heat-inactivated and live attenuated IAV strains administered intramuscularly and intranasally, respectively. Interestingly, in prime-boost immunization settings, the outcome of SEB administration depended strictly upon the time point at which this SAg was introduced. Accordingly, SEB injection before priming raised CD127highKLRG1low memory precursor frequencies and augmented the anamnestic responses of SEB-binding TCD8. By comparison, introducing SEB before boosting diminished recall responses to IAV-derived epitopes drastically and indiscriminately. This was accompanied by lower Ki67 and higher Fas, LAG-3 and PD-1 levels consistent with a pro-apoptotic and/or exhausted phenotype. Therefore, SAgs can have contrasting impacts on anti-IAV immunity depending on the naïve/memory status and the TCR composition of exposed TCD8. Finally, local administration of SEB or infection with SEB-producing S. aureus enhanced pulmonary TCD8 responses to IAV. Our findings have clear implications for superinfections and prophylactic vaccination. Exposure to bacterial superantigens (SAgs) is often a consequence of infection with common Gram-positive bacteria causing septic and toxic shock or food poisoning. How SAgs affect the magnitude, breadth and quality of infection/vaccine-elicited CD8+ T cell (TCD8) responses to respiratory viral pathogens, including influenza A viruses (IAVs), is far from clear. Also importantly, superinfections with IAVs and SAg-producing bacteria are serious clinical occurrences during seasonal and pandemic flu and require urgent attention. We demonstrate that two structurally distinct SAgs, including staphylococcal enterotoxin B (SEB), unexpectedly enhance primary TCD8 responses to ‘select’ IAV-derived epitopes depending on the TCR makeup of the responding clones. Intriguingly, the timing of exposure to SEB dictates the outcome of prime-boost immunization. Seeing a SAg before priming raises memory precursor frequencies and augments anamnestic TCD8 responses. Conversely, a SAg encounter before boosting renders TCD8 prone to death or exhaustion and impedes recall responses, thus likely compromising heterosubtypic immunity to IAVs. Finally, local exposure to SEB increases the pulmonary response of immunodominant IAV-specific TCD8. These findings shed new light on how bacterial infections and SAgs influence the effectiveness of anti-IAV TCD8 responses, and have, as such, wide-ranging implications for preventative vaccination and infection control.
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Affiliation(s)
- Courtney E. Meilleur
- Department of Microbiology and Immunology, Western University, London, Ontario, Canada
| | - Arash Memarnejadian
- Department of Microbiology and Immunology, Western University, London, Ontario, Canada
| | - Adil N. Shivji
- Department of Microbiology and Immunology, Western University, London, Ontario, Canada
| | - Jenna M. Benoit
- Department of Microbiology and Immunology, Western University, London, Ontario, Canada
| | - Stephen W. Tuffs
- Department of Microbiology and Immunology, Western University, London, Ontario, Canada
| | - Tina S. Mele
- Division of General Surgery, Department of Surgery, Western University, London, Ontario, Canada
- Division of Critical Care Medicine, Department of Medicine, Western University, London, Ontario, Canada
| | - Bhagirath Singh
- Department of Microbiology and Immunology, Western University, London, Ontario, Canada
- Lawson Health Research Institute, London, Ontario, Canada
- Centre for Human Immunology, Western University, London, Ontario, Canada
| | - Jimmy D. Dikeakos
- Department of Microbiology and Immunology, Western University, London, Ontario, Canada
| | - David J. Topham
- David H. Smith Center for Vaccine Biology and Immunology, Department of Microbiology and Immunology, University of Rochester Medical Center, Rochester, New York, United States of America
| | - Hong-Hua Mu
- Division of Rheumatology, Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City, Utah, United States of America
| | - Jack R. Bennink
- Viral Immunology Section, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, United States of America
| | - John K. McCormick
- Department of Microbiology and Immunology, Western University, London, Ontario, Canada
- Lawson Health Research Institute, London, Ontario, Canada
- Centre for Human Immunology, Western University, London, Ontario, Canada
| | - S. M. Mansour Haeryfar
- Department of Microbiology and Immunology, Western University, London, Ontario, Canada
- Division of General Surgery, Department of Surgery, Western University, London, Ontario, Canada
- Lawson Health Research Institute, London, Ontario, Canada
- Centre for Human Immunology, Western University, London, Ontario, Canada
- Division of Clinical Immunology & Allergy, Department of Medicine, Western University, London, Ontario, Canada
- * E-mail:
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3
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Yang WX, Zhu X, Yu FL, Zhang T, Lin N, Liu TT, Zhao FF, Liu Y, Xia H, Guan JC. Decreased Vβ8.2 T-cells in neonatal rats exposed prenatally to Staphylococcal enterotoxin B are further deleted by restimulation in an in vitro cultured thymus. Mol Med Rep 2014; 10:989-94. [PMID: 24865816 DOI: 10.3892/mmr.2014.2270] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2013] [Accepted: 04/25/2014] [Indexed: 11/06/2022] Open
Abstract
Staphylococcal enterotoxin B (SEB) administration during adulthood can cause the anergy or deletion of variable portion of the ? chain (V?)?expressing T cells. However, the effect of maternal SEB administration during pregnancy on the thymocytes of neonatal rats remains to be elucidated. In the present study, pregnant rats at gestational day 16 were intravenously injected with 15 µg SEB. The present study revealed that prenatal exposure of SEB significantly increased the proportion of cluster of differentiation (CD)4?single positive (SP) T cells and decreased the proportions of CD8?SP, CD4+ V?8.2+ and CD8+ V?8.2+ T cells in the thymus of neonatal rats between day 0 and 5 after delivery. In an in vitro cultured thymus, SEB restimulation significantly increased the proportion of double positive cells and decreased the proportions of CD4?SP, CD8?SP, CD4+ V?8.2+ and CD8+ V?8.2+ T cells. Furthermore, the decreased V?8.2+ T?cells in neonatal rats exposed prenatally to SEB were further deleted by SEB restimulation in an in vitro cultured thymus. These data suggested the special response pattern of the remaining SEB?specific T cells to SEB restimulation in neonatal rats exposed prenatally to SEB.
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Affiliation(s)
- Wen-Xuan Yang
- Anhui Key Laboratory of Infection and Immunity, Bengbu Medical College, Bengbu, Anhui 233030, P.R. China
| | - Xiang Zhu
- Anhui Key Laboratory of Infection and Immunity, Bengbu Medical College, Bengbu, Anhui 233030, P.R. China
| | - Feng-Ling Yu
- Anhui Key Laboratory of Infection and Immunity, Bengbu Medical College, Bengbu, Anhui 233030, P.R. China
| | - Tao Zhang
- Anhui Key Laboratory of Infection and Immunity, Bengbu Medical College, Bengbu, Anhui 233030, P.R. China
| | - Na Lin
- Anhui Key Laboratory of Infection and Immunity, Bengbu Medical College, Bengbu, Anhui 233030, P.R. China
| | - Ting-Ting Liu
- Anhui Key Laboratory of Infection and Immunity, Bengbu Medical College, Bengbu, Anhui 233030, P.R. China
| | - Fang-Fang Zhao
- Anhui Key Laboratory of Infection and Immunity, Bengbu Medical College, Bengbu, Anhui 233030, P.R. China
| | - Yong Liu
- Anhui Key Laboratory of Infection and Immunity, Bengbu Medical College, Bengbu, Anhui 233030, P.R. China
| | - Hui Xia
- Anhui Key Laboratory of Infection and Immunity, Bengbu Medical College, Bengbu, Anhui 233030, P.R. China
| | - Jun-Chang Guan
- Anhui Key Laboratory of Infection and Immunity, Bengbu Medical College, Bengbu, Anhui 233030, P.R. China
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Abstract
Respiratory syncytial virus (RSV) is the leading cause of lower respiratory tract viral disease in infants and young children. Presently, there are no explicit recommendations for RSV treatment apart from supportive care. The virus is therefore responsible for an estimated 160,000 deaths per year worldwide. Despite half a century of dedicated research, there remains no licensed vaccine product. Herein are described past and current efforts to harness innate and adaptive immune potentials to combat RSV. A plethora of candidate vaccine products and strategies are reviewed. The development of a successful RSV vaccine may ultimately stem from attention to historical lessons, in concert with an integral partnering of immunology and virology research fields.
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Affiliation(s)
- Julia L Hurwitz
- Department of Infectious Diseases, St Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USA.
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5
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Abstract
In his clonal selection theory, Frank Macfarlane Burnet predicted that autoreactive lymphocytes are deleted to prevent autoimmunity. This and other principles of lymphocyte behavior outlined by Burnet guided many studies that lead to our current understanding of thymic selection. Thus, when the genetic mutation responsible for autoimmune polyglandular syndrome type 1 was mapped to the autoimmune regulator (AIRE) gene, and Aire was found to be highly expressed in thymic epithelium, studying the role of Aire in negative selection made sense in the context of modern models of thymic selection. We now know Aire is a transcription factor required for the expression of many tissue-specific antigens (TSAs) in the thymus. In the absence of functional Aire, human patients and mice develop multi-organ autoimmune disease because of a defect in thymic negative selection. In addition to its role in the thymus, recent work in our lab suggests that extrathymic Aire-expressing cells have an important role in the clonal deletion of autoreactive CD8+ T cells. In this review, we summarize the latest studies on thymic and peripheral Aire-expressing cells, as well as other TSA-expressing stromal cell populations in peripheral lymphoid organs. We also discuss theoretical differences in thymic and peripheral Aire function that warrant further studies.
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Affiliation(s)
- Ruth T Taniguchi
- Diabetes Center, University of California, San Francisco, San Francisco, CA 94143-0540, USA
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Montalto M, D'Onofrio F, Santoro L, Gallo A, Gasbarrini A, Gasbarrini G. Autoimmune enteropathy in children and adults. Scand J Gastroenterol 2010; 44:1029-36. [PMID: 19255930 DOI: 10.1080/00365520902783691] [Citation(s) in RCA: 72] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
Autoimmune enteropathy is a rare disorder characterized by severe and protracted diarrhea, weight loss from malabsorption and immune-mediated damage to the intestinal mucosa, generally occurring in infants and young children, although some cases of adult onset have been reported in the literature. Pathogenetic mechanisms involve immunological disorders, in which the presence of antienterocyte autoantibodies, although detected since first description, seems now to be secondary. As occurs frequently in autoimmunity, subjects with autoimmune enteropathy may be affected by other autoimmune disorders, sometimes leading to particular forms, i.e. the IPEX syndrome and the APECED syndrome. The prognosis of autoimmune enteropathy patients depends on the severity of digestive symptoms (including fecal output), on the severity and extension of histological lesions along the gastrointestinal apparatus, and on the presence of extra-intestinal involvement. Management of autoimmune enteropathy patients is based on nutritional support and adequate hydration to ensure optimal growth and development, together with immunosuppressive therapy. Recently, biological agents have been introduced, with apparent beneficial effects.
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Affiliation(s)
- Massimo Montalto
- Institute of Internal Medicine, Catholic University, Rome, Italy.
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Acha-Orbea H, Held W, Scarpellino L, Shakhov AN. Mls: A Link Between Immunology and Retrovirology. Int Rev Immunol 2009; 8:327-36. [PMID: 1351535 DOI: 10.3109/08830189209053516] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
The nature of the mysterious minor lymphocyte stimulating (Mls) antigens has recently been clarified. These molecules which were key elements for our current understanding of immune tolerance, have a strong influence on the mouse immune system and are encoded by the open reading frame (orf) of endogenous and exogenous mouse mammary tumor viruses (MMTV's). The knowledge that these antigens are encoded by cancerogenic retroviruses opens an interdisciplinary approach for understanding the mechanisms of immune responses and immune tolerance, retroviral carcinogenesis, and retroviral strategies for infection.
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MESH Headings
- Amino Acid Sequence
- Animals
- Antigens, Viral/immunology
- CD4-Positive T-Lymphocytes/immunology
- Mammary Tumor Virus, Mouse/genetics
- Mammary Tumor Virus, Mouse/immunology
- Minor Lymphocyte Stimulatory Antigens/genetics
- Minor Lymphocyte Stimulatory Antigens/immunology
- Molecular Sequence Data
- Open Reading Frames
- Proviruses/genetics
- Receptors, Antigen, T-Cell, alpha-beta/genetics
- Receptors, Antigen, T-Cell, alpha-beta/immunology
- T-Lymphocytes, Regulatory/immunology
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Affiliation(s)
- H Acha-Orbea
- Ludwig Institute for Cancer Research, Lausanne Branch, Epalinges, Switzerland
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8
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Lönnqvist A, Ostman S, Almqvist N, Hultkrantz S, Telemo E, Wold AE, Rask C. Neonatal exposure to staphylococcal superantigen improves induction of oral tolerance in a mouse model of airway allergy. Eur J Immunol 2009; 39:447-56. [PMID: 19130476 DOI: 10.1002/eji.200838418] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Abstract
The hygiene hypothesis suggests that lack of microbial stimulation in early infancy may lead to allergy, but it has been difficult to identify particular protective microbial exposures. We have observed that infants colonised in the first week(s) of life with Staphylococcus aureus have lower risk of developing food allergy. As many S. aureus strains produce superantigens with T-cell stimulating properties, we here investigate whether neonatal mucosal exposure to superantigen could influence the capacity to develop oral tolerance and reduce sensitisation and allergy. BALB/c mice were exposed to staphylococcal enterotoxin A (SEA) as neonates and fed with OVA as adults, prior to sensitisation and i.n. OVA challenge. Our results show that SEA pre-treated mice are more efficiently tolerised by OVA feeding, as shown by lower lung-cell infiltration and antigen-specific IgE response in the SEA pre-treated mice, compared with sham-treated mice. This was not due to deletion or anergy of lymphocytes by SEA treatment, because the SEA pre-treated mice that were fed with PBS showed similar inflammatory response as the sham-treated PBS-fed mice. Our results suggest that strong T-cell activation in infancy conditions the mucosal immune system and promotes development of oral tolerance.
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Affiliation(s)
- Anna Lönnqvist
- Department of Clinical Bacteriology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
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9
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The impact of circulating dendritic cells on the development and differentiation of thymocytes. Immunol Cell Biol 2008; 87:39-45. [PMID: 19048018 DOI: 10.1038/icb.2008.86] [Citation(s) in RCA: 42] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
Central tolerance is established through the negative selection of self-reactive thymocytes and the induction of T-regulatory cells (T-regs). A role for thymic epithelial cells in mediating both negative selection and T-reg induction has been clearly shown. The role of thymic dendritic cells (DCs) in these processes has not been clearly determined but has been the focus of recent studies. Thymic DCs include two conventional DC (cDC) subtypes, CD8(lo)Sirpalpha(hi/+) (CD8(lo)Sirpalpha(+) herein) and CD8(hi)Sirpalpha(lo/-) (CD8(hi)Sirpalpha(-) herein). It has been shown that these DC subsets have distinct developmental origins, the CD8(hi)Sirpalpha(-) cDCs developing intra-thymically and the CD8(lo)Sirpalpha(+) migrating into the thymus from the periphery. Furthermore, an important role for thymic DCs in the induction of T-regs has been shown. In this review, the role of DCs in the development and education of T cells in the thymus will be reviewed, with emphasis on the role of circulatory DCs in mediating these processes.
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10
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Hodes RJ, Abe R. Mouse endogenous superantigens: Ms and Mls-like determinants encoded by mouse retroviruses. CURRENT PROTOCOLS IN IMMUNOLOGY 2008; Appendix 1:Appendix 1F. [PMID: 18432642 DOI: 10.1002/0471142735.ima01fs17] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/07/2022]
Abstract
Commonly used inbred mouse strains express different combinations of integrated mouse mammary tumor proviruses (MMTV). This appendix summarizes the proviruses that have been detected. The reported functional properties of those MMTV proviral products which have been identified as superantigens are also summarized, including the ability to elicit primary or secondary T cell responses and to induce Vb-specific clonal deletion during T cell differentiation. In addition, the amino acid sequences of putative ORF gene products of different MMTV are compared.
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Affiliation(s)
- R J Hodes
- National Cancer Institute, Bethesda, Maryland, USA
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11
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What do we know about the mechanisms of elimination of autoreactive T and B cells and what challenges remain. Immunol Cell Biol 2007; 86:57-66. [PMID: 18026176 DOI: 10.1038/sj.icb.7100141] [Citation(s) in RCA: 55] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
Tolerance to self-antigens within the adaptive immune system is safeguarded, at least in part, through deletion of autoreactive T and B lymphocytes. This deletion can occur during the development of these cells in primary lymphoid organs, the thymus or bone marrow, respectively, or at the mature stage in peripheral lymphoid tissues. Deletion of autoreactive lymphocytes is achieved to a large extent through apoptotic cell death. This review describes current understanding of the mechanisms that mediate apoptosis of autoreactive lymphocytes during their development in primary lymphoid organs and during their activation in the periphery. In particular, we discuss the roles of the proapoptotic Bcl-2 family member Bim and the small family of Nur77-related transcriptional regulators in lymphocyte negative selection. Finally, we speculate on the processes that may lead to the activation of Bim when antigen receptors are activated on autoreactive T or B cells.
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12
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Oliver PM, Cao X, Worthen GS, Shi P, Briones N, MacLeod M, White J, Kirby P, Kappler J, Marrack P, Yang B. Ndfip1 protein promotes the function of itch ubiquitin ligase to prevent T cell activation and T helper 2 cell-mediated inflammation. Immunity 2006; 25:929-40. [PMID: 17137798 PMCID: PMC2955961 DOI: 10.1016/j.immuni.2006.10.012] [Citation(s) in RCA: 113] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2006] [Revised: 08/07/2006] [Accepted: 10/05/2006] [Indexed: 12/18/2022]
Abstract
Nedd4 family interacting protein-1 (Ndfip1) is a protein whose only known function is that it binds Nedd4, a HECT-type E3 ubiquitin ligase. Here we show that mice lacking Ndfip1 developed severe inflammation of the skin and lung and died prematurely. This condition was due to a defect in Ndfip1(-/-) T cells. Ndfip1(-/-) T cells were activated, and they proliferated and adopted a T helper 2 (Th2) phenotype more readily than did their Ndfip1(+/+) counterparts. This phenotype resembled that of Itchy mutant mice, suggesting that Ndfip1 might affect the function of Itch, an E3 ubiquitin ligase. We show that T cell activation promoted both Ndfip1 expression and its association with Itch. In the absence of Ndfip1, JunB half-life was prolonged after T cell activation. Thus, in the absence of Ndfip1, Itch is inactive and JunB accumulates. As a result, T cells produce Th2 cytokines and promote Th2-mediated inflammatory disease.
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Affiliation(s)
- Paula M. Oliver
- Howard Hughes Medical Institute, National Jewish Medical and Research Center and University of Colorado Health Sciences Center, Denver, Colorado 80206
- Department of Immunology, University of Colorado Health Sciences Center, Denver, Colorado 80206
| | - Xiao Cao
- Department of Obstetrics and Gynecology, Carver College of Medicine, University of Iowa, Iowa City, Iowa 52242
| | - George Scott Worthen
- Department of Medicine, University of Colorado Health Sciences Center, Denver, Colorado 80206
| | - Peijun Shi
- Department of Obstetrics and Gynecology, Carver College of Medicine, University of Iowa, Iowa City, Iowa 52242
| | - Natalie Briones
- Department of Medicine, University of Colorado Health Sciences Center, Denver, Colorado 80206
| | - Megan MacLeod
- Howard Hughes Medical Institute, National Jewish Medical and Research Center and University of Colorado Health Sciences Center, Denver, Colorado 80206
- Department of Immunology, University of Colorado Health Sciences Center, Denver, Colorado 80206
| | - Janice White
- Howard Hughes Medical Institute, National Jewish Medical and Research Center and University of Colorado Health Sciences Center, Denver, Colorado 80206
| | - Patricia Kirby
- Department of Pathology, Carver College of Medicine, University of Iowa, Iowa City, Iowa 52242
| | - John Kappler
- Howard Hughes Medical Institute, National Jewish Medical and Research Center and University of Colorado Health Sciences Center, Denver, Colorado 80206
- Department of Immunology, University of Colorado Health Sciences Center, Denver, Colorado 80206
- Department of Pharmacology, University of Colorado Health Sciences Center, Denver, Colorado 80206
| | - Philippa Marrack
- Howard Hughes Medical Institute, National Jewish Medical and Research Center and University of Colorado Health Sciences Center, Denver, Colorado 80206
- Department of Immunology, University of Colorado Health Sciences Center, Denver, Colorado 80206
- Department of Biochemistry and Molecular Genetics, University of Colorado Health Sciences Center, Denver, Colorado 80206
| | - Baoli Yang
- Department of Obstetrics and Gynecology, Carver College of Medicine, University of Iowa, Iowa City, Iowa 52242
- Correspondence:
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13
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Hirose S, Jiang Y, Nishimura H, Shirai T. Significance of MHC class II haplotypes and IgG Fc receptors in SLE. ACTA ACUST UNITED AC 2006; 28:163-74. [PMID: 16972051 DOI: 10.1007/s00281-006-0036-1] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2006] [Accepted: 07/04/2006] [Indexed: 10/24/2022]
Abstract
Systemic lupus erythematosus (SLE) is a systemic antibody-mediated autoimmune disease that develops under the control of multiple susceptibility genes. Genetic studies in murine and human SLE have identified several chromosomal intervals that contain candidate susceptibility genes. However, the ultimate identification of the genes and their roles in disease process need much further investigation. Spontaneous murine SLE models provide useful tools in this respect. In this chapter, we show this line of investigation, particularly focusing on the roles of major histocompatibility complex (MHC) class II and immunoglobulin G Fc receptors (FcgammaRs). The existence of high-affinity autoantibodies is evidence that autoimmunity in SLE is antigen-driven. Thereby, MHC class II haplotypes have been implicated in SLE susceptibility; however, because of the linkage disequilibrium that exists among the class I, II and III genes within the MHC complex, it has been difficult to discriminate the relative contributions of individual loci. On the other hand, the extent of antibody synthesis upon antigen stimulation and associated inflammatory cascades are controlled in several ways by the balance of stimulatory and inhibitory signaling molecules on immune cells. Stimulatory/inhibitory FcgammaRs mediate one such mechanism, and there are reports indicating the association between polymorphic FcgammaRs and SLE. However, as stimulatory and inhibitory FcgammaRs cluster on the telomeric chromosome 1, the absolute contribution of individual genes has been difficult to dissect. In studies of genetic dissection using interval-congenic and intragenic recombinant mouse strains of SLE models, we show evidence and discuss how and to what extent MHC class II molecules and stimulatory/inhibitory FcgammaRs are involved in SLE susceptibility.
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Affiliation(s)
- Sachiko Hirose
- Department of Pathology, Juntendo University School of Medicine, 2-1-1, Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan.
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Lee JS, Cho ML, Jhun JY, Min SY, Ju JH, Yoon CH, Min JK, Park SH, Kim HY, Cho YG. Antigen-specific expansion of TCR Vbeta3+ CD4+ T cells in the early stage of collagen-induced arthritis and its arthritogenic role in DBA/1J mice. J Clin Immunol 2006; 26:204-12. [PMID: 16783460 DOI: 10.1007/s10875-006-9012-8] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2005] [Accepted: 01/11/2006] [Indexed: 10/24/2022]
Abstract
To investigate type II collagen (CII)-specific CD4+ T cell receptors involving in Collagen-induced arthritis (CIA) in DBA/1J mice as a model of rheumatoid arthritis in humans, TCR Vbeta usage in draining lymph nodes (dLNs) was assessed by flow cytometric analysis at 3, 5, and 8 weeks after bovine CII immunizations. In the early stage of CIA, the draining lymph node CD4+ T cells from CIA mice showed a higher proportion of CD4+ Vbeta3+ subsets compared with those from control mice. The CD4+ Vbeta3+ T cells were specifically and primarily expanded by antigen-specific stimulation in in vitro culture of dLNs lymphocytes and splenocytes from CIA mice. In addition, CII-reactive response was observed when CD4+ Vbeta3+ T cells were added to a non-responding T cell population. The adoptive transfer of CD4+ Vbeta3+ T cells produced exaggerated arthritis compared with that in the control group. Our results indicate that CD4+ Vbeta3+ T cells, which were selectively expanded in dLN of CIA mice, play a pivotal role in CIA pathogenesis.
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Affiliation(s)
- Jae-Seon Lee
- Department of Medicine, Division of Rheumatology, Center for Rheumatoid Diseases, Catholic Research Institutes of Medical Sciences, Catholic University of Korea, Seoul, Republic of Korea
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15
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Terszowski G, Müller SM, Bleul CC, Blum C, Schirmbeck R, Reimann J, Pasquier LD, Amagai T, Boehm T, Rodewald HR. Evidence for a functional second thymus in mice. Science 2006; 312:284-7. [PMID: 16513945 DOI: 10.1126/science.1123497] [Citation(s) in RCA: 107] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/02/2022]
Abstract
The thymus organ supports the development of T cells and is located in the thorax. Here, we report the existence of a second thymus in the mouse neck, which develops after birth and grows to the size of a small lymph node. The cervical thymus had a typical medulla-cortex structure, was found to support T cell development, and could correct T cell deficiency in athymic nude mice upon transplantation. The identification of a regular second thymus in the mouse may provide evolutionary links to thymus organogenesis in other vertebrates and suggests a need to reconsider the effect of thoracic thymectomy on de novo T cell production.
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16
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Chen YT, Kung JT. CD1d-Independent Developmental Acquisition of Prompt IL-4 Gene Inducibility in Thymus CD161(NK1)−CD44lowCD4+CD8− T Cells Is Associated with Complementarity Determining Region 3-Diverse and Biased Vβ2/Vβ7/Vβ8/Vα3.2 T Cell Receptor Usage. THE JOURNAL OF IMMUNOLOGY 2005; 175:6537-50. [PMID: 16272308 DOI: 10.4049/jimmunol.175.10.6537] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
Among Ag-inexperienced naive T cells, the CD1d-restricted NKT cell that uses invariant TCR-alpha-chain is the most widely studied cell capable of prompt IL-4 inducibility. We show in this study that thymus CD161-CD44lowCD4+CD8- T cells promptly produce IL-4 upon TCR stimulation, a response that displays biased Vbeta(2/7/8) and Valpha3.2 TCR usage. The association of Vbeta family bias and IL-4 inducibility in thymus CD161-CD44lowCD4+CD8- T cells is found for B6, B10, BALB/c, CBA, B10.A(4R), and ICR mouse strains. Despite reduced IL-4 inducibility, there is a similarly biased Vbeta(2/7/8) TCR usage by IL-4 inducibility+ spleen CD161-CD44lowCD4+CD8- T cells. Removal of alpha-galacotosylceramide/CD1d-binding cells from CD161-CD44lowCD4+CD8- thymocytes does not significantly affect their IL-4 inducibility. The development of thymus CD161-CD44lowCD4+CD8- T cells endowed with IL-4 inducibility and their associated use of Vbeta(2/7/8) are beta2-microglobulin-, CD1d-, and p59fyn-independent. Thymus CD161-CD44lowCD4+CD8- T cells produce low and no IFN-gamma inducibility in response to TCR stimulation and to IL-12 + IL-18, respectively, and they express diverse complementarity determining region 3 sequences for both TCR-alpha- and -beta-chains. Taken together, these results demonstrate the existence of a NKT cell distinct, TCR-repertoire diverse naive CD4+ T cell subset capable of prompt IL-4 inducibility. This subset has the potential to participate in immune response to a relatively large number of Ags. The more prevalent nature of this unique T cell subset in the thymus than the periphery implies roles it might play in intrathymic T cell development and may provide a framework upon which mechanisms of developmentally regulated IL-4 gene inducibility can be studied.
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MESH Headings
- Amino Acid Sequence
- Animals
- Antigens, CD1/metabolism
- Antigens, CD1d
- Antigens, Surface/metabolism
- Base Sequence
- CD4-Positive T-Lymphocytes/cytology
- CD4-Positive T-Lymphocytes/drug effects
- CD4-Positive T-Lymphocytes/immunology
- CD8-Positive T-Lymphocytes/cytology
- CD8-Positive T-Lymphocytes/drug effects
- CD8-Positive T-Lymphocytes/immunology
- Cell Differentiation
- Complementarity Determining Regions
- DNA/genetics
- Galactosylceramides/immunology
- Galactosylceramides/pharmacology
- Gene Expression Regulation
- Interleukin-4/genetics
- Interleukins/biosynthesis
- Killer Cells, Natural/cytology
- Killer Cells, Natural/drug effects
- Killer Cells, Natural/immunology
- Lectins, C-Type/metabolism
- Mice
- Mice, Inbred BALB C
- Mice, Inbred CBA
- Mice, Inbred ICR
- Mice, Transgenic
- Molecular Sequence Data
- NK Cell Lectin-Like Receptor Subfamily B
- RNA, Messenger/genetics
- RNA, Messenger/metabolism
- Receptors, Antigen, T-Cell, alpha-beta/genetics
- T-Lymphocyte Subsets/cytology
- T-Lymphocyte Subsets/drug effects
- T-Lymphocyte Subsets/immunology
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Affiliation(s)
- Yi-Ting Chen
- Graduate Institute of Immunology, College of Medicine, National Taiwan University, Taipei, Taiwan
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17
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Jiang H, Wu Y, Liang B, Zheng Z, Tang G, Kanellopoulos J, Soloski M, Winchester R, Goldstein I, Chess L. An affinity/avidity model of peripheral T cell regulation. J Clin Invest 2005; 115:302-12. [PMID: 15668735 PMCID: PMC544609 DOI: 10.1172/jci23879] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2004] [Accepted: 12/01/2004] [Indexed: 01/20/2023] Open
Abstract
We show in these studies that Qa-1-dependent CD8+ T cells are involved in the establishment and maintenance of peripheral self tolerance as well as facilitating affinity maturation of CD4+ T cells responding to foreign antigen. We provide experimental evidence that the strategy used by the Qa-1-dependent CD8+ T cells to accomplish both these tasks in vivo is to selectively downregulate T cell clones that respond to both self and foreign antigens with intermediate, not high or low, affinity/avidity. Thus, the immune system evolved to regulate peripheral immunity using a unified mechanism that efficiently and effectively permits the system to safeguard peripheral self tolerance yet promote the capacity to deal with foreign invaders.
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Affiliation(s)
- Hong Jiang
- Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, New York 10032, USA.
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18
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Zhang D, Fujio K, Jiang Y, Zhao J, Tada N, Sudo K, Tsurui H, Nakamura K, Yamamoto K, Nishimura H, Shira T, Hirose S. Dissection of the role of MHC class II A and E genes in autoimmune susceptibility in murine lupus models with intragenic recombination. Proc Natl Acad Sci U S A 2004; 101:13838-43. [PMID: 15361580 PMCID: PMC518842 DOI: 10.1073/pnas.0405807101] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2004] [Indexed: 11/18/2022] Open
Abstract
Systemic lupus erythematosus (SLE) is a multigenic autoimmune disease, and the major histocompatibility complex (MHC) class II polymorphism serves as a key genetic element. In SLE-prone (NZB x NZW)F(1) mice, the MHC H-2(d/z) heterozygosity (H-2(d) of NZB and H-2(z) of NZW) has a strong impact on disease; thus, congenic H-2(d/d) homozygous F(1) mice do not develop severe disease. In this study, we used Ea-deficient intra-H-2 recombination to establish A(d/d)-congenic (NZB x NZW)F(1) mice, with or without E molecule expression, and dissected the role of class II A and E molecules. Here we found that A(d/d) homozygous F(1) mice lacking E molecules developed severe SLE similar to that seen in wild-type F1 mice, including lupus nephritis, autoantibody production, and spontaneously occurring T cell activation. Additional evidence revealed that E molecules prevent the disease in a dose-dependent manner; however, the effect is greatly influenced by the haplotype of A molecules, because wild-type H-2(d/z) F(1) mice develop SLE, despite E molecule expression. Studies on the potential of dendritic cells to present a self-antigen chromatin indicated that dendritic cells from wild-type F(1) mice induced a greater response of chromatin-specific T cells than did those from A(d/d) F(1) mice, irrespective of the presence or absence of E molecules, suggesting that the self-antigen presentation is mediated by A, but not by E, molecules. Our mouse models are useful for analyzing the molecular mechanisms by which MHC class II regions regulate the process of autoimmune responses.
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Affiliation(s)
- Danqing Zhang
- Second Department of Pathology and Atopy Research Center, Juntendo University School of Medicine, Tokyo 113-8421, Japan
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19
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Maxwell JR, Rossi RJ, McSorley SJ, Vella AT. T cell clonal conditioning: a phase occurring early after antigen presentation but before clonal expansion is impacted by Toll-like receptor stimulation. THE JOURNAL OF IMMUNOLOGY 2004; 172:248-59. [PMID: 14688332 DOI: 10.4049/jimmunol.172.1.248] [Citation(s) in RCA: 43] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
After in vivo immunization, Ag-specific T cells disappear from circulation and become sequestered in lymphoid tissue where they encounter Ag presented by dendritic cells. In the same site and just after Ag presentation, they "disappear" a second time and we investigated this process. Using a mouse model of T cell deletion (without Toll-like receptor (TLR) stimulation) vs survival (with TLR stimulation), Ag-specific T cells indeed became undetectable by flow cytometry, however were readily detected by immunohistochemistry. Thus, whether or not the activated T cells were destined to delete or survive, they were difficult to extract from lymphoid tissue and did not disappear but in fact were abundantly present. Nevertheless, profound differences were observed during this time period when tolerizing conditions were compared with immunizing conditions. TLR stimulation induced an increase in CD25 expression, acquisition of surface MHC class II, and abnormally high increases in forward and side scatter of the peptide-specific T cells. Using a modified adoptive transfer approach, we demonstrated by flow cytometry that in the presence of TLR stimulation the Ag-specific T cells were tightly coupled to dendritic cells, explaining the unusual increases in size and granularity. Ultimately, these events induced the specific T cells to differentiate into memory cells. We postulate that this is a stage where T cells are either conditioned to survive or to delete depending upon the activation status of the innate immune system.
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Affiliation(s)
- Joseph R Maxwell
- Division of Immunology, University of Connecticut Health Center, 263 Farmington Avenue, Farmington, CT 06032, USA
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20
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Ohtani M, Azuma T, Yamazaki S, Yamakawa A, Ito Y, Muramatsu A, Dojo M, Yamazaki Y, Kuriyama M. Association of the HLA-DRB1 gene locus with gastric adenocarcinoma in Japan. Dig Liver Dis 2003; 35:468-72. [PMID: 12870731 DOI: 10.1016/s1590-8658(03)00218-4] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
BACKGROUND AND AIM Helicobacter pylori infection is associated with gastric adenocarcinoma, however, the odds ratio is relatively low. The aim of the present study was to investigate host genetic factors that increase the risk of gastric adenocarcinoma among H. pylori-infected individuals. METHODS A total of 70 patients with early gastric adenocarcinoma and 121 unrelated healthy controls were examined for H. pylori infection and HLA-DRB1 genotyping. The frequencies of HLA-DRB1 alleles were compared among groups. RESULTS The allele frequency of DRB1*04051 was significantly higher in patients with gastric adenocarcinoma (17.9%) than in controls (7.9%) (P(correct) = 0.045). The odds ratio of gastric adenocarcinoma associated with the presence of the HLA-DRB1*04051 allele compared with its absence was 2.55 (95% confidence limits, 1.35-4.83). This genetic risk was not associated with H. pylori infection. There was no significant difference in the HLA-DRB1 allele frequency between H. pylori-positive and H. pylori-negative controls. The frequency of genotypes that possessed the DRB1*04051 allele in gastric adenocarcinoma patients (34.3%) was significantly higher than that in H. pylori-negative controls (11.9%) (p = 0.0089) and H. pylori-positive controls (15.2%) (p = 0.0066). CONCLUSION These findings suggest that immunogenetic factors for susceptibility to gastric adenocarcinoma are present in the host, the HLA-DRB1*04051 allele is a host genetic risk factor for gastric adenocarcinoma, and that this genetic risk is independent of H. pylori infection.
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Affiliation(s)
- M Ohtani
- Second Department of Internal Medicine, Fukui Medical University, Matsuoka-cho, Yoshida-gun, Fukui 910-1193, Japan
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21
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Myers L, Takahashi C, Mittler RS, Rossi RJ, Vella AT. Effector CD8 T cells possess suppressor function after 4-1BB and Toll-like receptor triggering. Proc Natl Acad Sci U S A 2003; 100:5348-53. [PMID: 12695569 PMCID: PMC154348 DOI: 10.1073/pnas.0837611100] [Citation(s) in RCA: 54] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2002] [Indexed: 11/18/2022] Open
Abstract
To better understand how innate and adaptive immune responses interact with each other, we combined 4-1BB T cell costimulation with specific adjuvants to determine whether these treatments would influence specific T cell expansion and function in vivo. In the presence of 4-1BB ligation and Toll-like receptor 3 (TLR)3 and/or TLR4 triggering, CD8 T cell clonal expansion and survival was augmented profoundly. Specific T cells primed in vivo with TLR ligands responded normally to in vitro recall stimulus, but, surprisingly, copriming with 4-1BB costimulation significantly impaired the recall response even though many more specific effector T cells were rescued in vivo. Here, we demonstrate that the rescued CD8 T cells suppressed CD4 T cell proliferation via a type beta transforming growth factor-dependent mechanism. Thus, 4-1BB and TLR ligands induce survival of specific effector CD8 T cells with suppressive recall potential, which may explain the dual role that 4-1BB activation plays in mediating tumor clearance and prevention of autoimmune disease.
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Affiliation(s)
- Lara Myers
- Division of Immunology, University of Connecticut Health Center, Farmington, CT 06032, USA
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22
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Abstract
The thymus is the primary site of T-cell production early in life, and has now been shown to continue to function in both healthy and immunocompromised individuals late into life. Positive and negative selection occurring in the thymus are two of the most important processes that govern the development and specificity of peripheral T cells, including their restriction to self HLA and their ability to respond in an alloreactive manner. In the chimeric state that follows successful allogeneic stem-cell transplants, the specificity of alloreactive cells may be governed by either host- or recipient-derived cellular elements, as well as maturing lymphoid cells, which are, in turn, derived from donor stem cells or host cells surviving transplant conditioning. The ability to measure recent thymic emigrants via the detection of T-cell receptor excision circles has facilitated studies of thymic function in immunodeficient individuals, including HIV-1 infected subjects and recipients of autologous or allogeneic stem-cell transplant (SCT). These studies have now demonstrated that thymic function is likely to play a beneficial role in immune reconstitution in these settings, but have yet to clearly demonstrate what clinical variables are the most important determinants of thymic persistence. It is also not yet clear how much the degree of thymic function following allogeneic SCT influences the alloreactive T-cell repertoire, although studies in animal models and early clinical studies suggest that GvHD results in thymic injury and dysfunction. Future studies will further clarify how thymic function shapes the repertoire of T cells that mediate alloreactivity, as well as protective pathogen-specific immune responses, following SCT. Finally, these studies will also demonstrate whether endogenous mediators of thymic function could be selectively applied to regulate post-SCT thymic function and alloreactivity.
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Affiliation(s)
- K V Komanduri
- Department of Blood and Marrow Transplantation, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
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23
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Videbaek N, Harach S, Phillips J, Hutchings P, Ozegbe P, Michelsen BK, Cooke A. An islet-homing NOD CD8+ cytotoxic T cell clone recognizes GAD65 and causes insulitis. J Autoimmun 2003; 20:97-109. [PMID: 12657523 DOI: 10.1016/s0896-8411(03)00003-9] [Citation(s) in RCA: 18] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
T cells play a central role in the development of diabetes both in man and in the non-obese diabetic (NOD) mouse. Both the CD4(+) and CD8(+) subsets of T cells are required for the normal development of IDDM in NOD mice. Islet reactive CD4(+) T cells play a clear pathogenic role as evidenced from the isolation of diabetogenic CD4(+) T cell clones. CD8(+) T cells seem to be involved in the initiation of diabetes as lack of these cells leads to protection from diabetes. We have isolated a GAD(65) reactive, cytotoxic CD8(+) T cell clone R1 that produces large quantities of IFNgamma and accelerates the onset of insulitis. This clone proliferates and produces IFNgamma in response to GAD(65) presenting APCs and kills GAD(65) presenting targets. Furthermore, it expresses TNFalpha, CD25, CD28, CD44, CD45 and LFA1, but not CD95L This is the first example of a GAD(65)specific CD8(+) T cell clone that accelerates the onset of the insulitis, although it does not appear to accelerate the onset of diabetes.
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Affiliation(s)
- Nicoline Videbaek
- Hagedorn Research Institute, Niels Steensensvej 6, DK 2820, Gentofte, Denmark
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24
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Zhang L, Lizzio EF, Gubina E, Chen T, Mostowski H, Kozlowski S. Organ-specific cytokine polarization induced by adoptive transfer of transgenic T cells. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2002; 169:5514-21. [PMID: 12421927 DOI: 10.4049/jimmunol.169.10.5514] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
There are two distinct phenotypes of T cell cytokine responses that lead to different effector functions and different outcomes in disease processes. Although evidence suggests a possible role of the local microenvironment in the differentiation or localization of T cells with these phenotypes, there are no examples of divergent T cell cytokine phenotypes with the same Ag specificity concurrently existing in different tissue compartments. Using a CD8(+) T cell adoptive transfer model for graft-vs-host disease, we demonstrate that a potent type 2 cytokine response develops in the spleen while a potent type 1 cytokine response simultaneously develops in the testis. These experiments demonstrate for the first time that cytokine production can be oppositely polarized in different organs of the same individual. This may have important implications for organ-specific pathology in infection or autoimmunity: infections or autoimmune diseases that affect multiple organs may have heterogeneity in tissue cytokine responses that is not revealed in systemic lymphocyte cytokine responses. Therefore, attempts to modulate the immune response phenotype may ameliorate pathology in one organ while exacerbating pathology in another.
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Affiliation(s)
- Lei Zhang
- Divisions of Monoclonal Antibodies, Center for Biologics Evaluation and Research, Food and Drug Administration, Building 29B, 29 Lincoln Drive, Bethesda, MD 20892, USA
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25
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Maxwell JR, Ruby C, Kerkvliet NI, Vella AT. Contrasting the roles of costimulation and the natural adjuvant lipopolysaccharide during the induction of T cell immunity. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2002; 168:4372-81. [PMID: 11970979 DOI: 10.4049/jimmunol.168.9.4372] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
The requirements for circumventing tolerance induction in favor of memory T cell development are poorly understood. Although two signals (Ag and costimulation) are necessary to drive effective T cell clonal expansion, few memory T cells remain after the response wanes. The adjuvant LPS can increase numbers of long-lived Ag-specific T cells, but its mechanism of action is not understood. In this report, it is shown that LPS, when combined with two-signal stimulation, profoundly enhances T cell survival in vivo. This survival does not appear to be dependent on the cytokines TNF-alpha, IL-1 beta, IL-6, and IFN-gamma, nor is it dependent on the transcription factor NF-kappa B. However, in vivo proliferation of NF-kappa B-deficient T cells was comparable to that of wild-type T cells, yet their early accumulation in the lymph nodes was severely reduced unless the mice were treated with LPS and an agonistic CD40 mAb. Most importantly, we found that activation of two different costimulatory signals, CD40 and OX40, could not substitute for LPS in rescuing T cells from peripheral deletion. Perhaps surprisingly, these data show that LPS delivers a qualitatively different signal than multiple costimulatory signals.
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Affiliation(s)
- Joseph R Maxwell
- Division of Immunology, University of Connecticut Health Center, Farmington, CT 06030, USA
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26
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Chiu PP, Jevnikar AM, Danska JS. Genetic control of T and B lymphocyte activation in nonobese diabetic mice. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2001; 167:7169-79. [PMID: 11739540 DOI: 10.4049/jimmunol.167.12.7169] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
Abstract
Type 1 diabetes in nonobese diabetic (NOD) mice is characterized by the infiltration of T and B cells into pancreatic islets. T cells bearing the TCR Vbeta3 chain are disproportionately represented in the earliest stages of islet infiltration (insulitis) despite clonal deletion of most Vbeta3(+) immature thymocytes by the mammary tumor virus-3 (Mtv-3) superantigen (SAg). In this report we showed that a high frequency of NOD Vbeta3(+) T cells that escape deletion are activated in vivo and that this phenotype is linked to the Mtv-3 locus. One potential mechanism of SAg presentation to peripheral T cells is by activated B cells. Consistent with this idea, we found that NOD mice harbor a significantly higher frequency of activated B cells than nondiabetes-prone strains. These activated NOD B cells expressed cell surface molecules consistent with APC function. At the molecular level, the IgH repertoire of activated B cells in NOD mice was equivalent to resting B cells, suggesting a polyclonal response in vivo. Genetic analysis of the activated B cell phenotype showed linkage to Idd1, the NOD MHC haplotype (H-2(g7)). Finally, Vbeta3(+) thymocyte deletion and peripheral T cell activation did not require B cells, suggesting that other APC populations are sufficient to generate both Mtv-3-linked phenotypes. These data provide insight into the genetic regulation of NOD autoreactive lymphocyte activation that may contribute to failure of peripheral tolerance and the pathogenesis of type I diabetes.
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MESH Headings
- Animals
- Antigens, CD/analysis
- Antigens, Differentiation, T-Lymphocyte/analysis
- Antigens, Viral/genetics
- Antigens, Viral/immunology
- B-Lymphocytes/immunology
- Cells, Cultured
- Chromosome Mapping
- Clonal Deletion
- Diabetes Mellitus, Type 1/genetics
- Diabetes Mellitus, Type 1/immunology
- Flow Cytometry
- Genes, T-Cell Receptor beta
- Immunoglobulin Variable Region/genetics
- Lectins, C-Type
- Lymphocyte Activation
- Major Histocompatibility Complex
- Mice
- Mice, Inbred NOD
- Proviruses/immunology
- Receptors, Antigen, T-Cell/metabolism
- Superantigens/genetics
- Superantigens/immunology
- T-Lymphocytes/immunology
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Affiliation(s)
- P P Chiu
- Program in Developmental Biology, Hospital for Sick Children Research Institute, Department of Surgery, University of Toronto, Toronto, Canada
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27
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Sant'Angelo DB, Cresswell P, Janeway CA, Denzin LK. Maintenance of TCR clonality in T cells expressing genes for two TCR heterodimers. Proc Natl Acad Sci U S A 2001; 98:6824-9. [PMID: 11381132 PMCID: PMC34437 DOI: 10.1073/pnas.121179998] [Citation(s) in RCA: 30] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/11/2001] [Indexed: 11/18/2022] Open
Abstract
T cell receptor (TCR) allelic exclusion is believed to be primarily mediated by suppression of further recombination at the TCR locus after the expression of a functional TCR protein. Genetic allelic exclusion has been shown to be leaky for the beta chain and, more commonly, for the alpha chain. Here, we demonstrate an additional mechanism by which T cells can maintain monoclonality. T cells from double TCR transgenic mice express only one or the other of the two available TCRs at the cell surface. This "functional allelic exclusion" is apparently due to control of the TCR assembly process because these T cells express RNA and protein for all four transgenic TCR proteins. Lack of cell surface expression of the second TCR may be controlled by a failure to assemble the TCR heterodimer.
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MESH Headings
- Alleles
- Dimerization
- Flow Cytometry
- Humans
- RNA, Messenger/analysis
- Receptors, Antigen, T-Cell, alpha-beta/chemistry
- Receptors, Antigen, T-Cell, alpha-beta/genetics
- Receptors, Antigen, T-Cell, alpha-beta/physiology
- Reverse Transcriptase Polymerase Chain Reaction
- T-Lymphocytes/metabolism
- Transgenes
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Affiliation(s)
- D B Sant'Angelo
- Immunology Program, Memorial Sloan-Kettering Cancer Center, Weill Graduate School of Medical Sciences of Cornell University, New York, NY 10021, USA. d-sant'
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28
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Takahashi C, Mittler RS, Vella AT. Differential clonal expansion of CD4 and CD8 T cells in response to 4-1BB ligation: contribution of 4-1BB during inflammatory responses. Immunol Lett 2001; 76:183-91. [PMID: 11306146 DOI: 10.1016/s0165-2478(01)00188-2] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
Abstract
Cell surface proteins of the tumor necrosis factor (TNF) family of receptors have been intimately involved in inducing T cell death. A feature of these family members that is less well studied is their ability to rescue T cells from apoptosis. One such member is 4-1BB; an activation induced surface receptor on CD4 and CD8 T cells. This study demonstrates that the costimulatory effects of 4-1BB, which was found to enhance clonal expansion, required cross-linking of the receptor. The survival of the activated CD8 T cells following expansion was not associated with an increase in Bcl-2 expression. Provided that 4-1BB signaling was present, the amplification of activated CD8 T cell growth in vivo was independent of CD28 ligation. In vivo clonal expansion of activated CD4 T cells, however, was not as responsive to 4-1BB cross-linking. Moreover, 4-1BB-induced expansion was comparable to that mediated by LPS which can incite multiple costimulatory signals. Furthermore, LPS-mediated growth and survival of superantigen (SAg) stimulated T cells appeared to be partially dependent on interactions between 4-1BB and 4-1BB ligand (4-1BBL).
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Affiliation(s)
- C Takahashi
- Department of Microbiology, 220 Nash Hall, Oregon State University, Corvallis, OR 97331, USA
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Wu CH, Ouyang EC, Walton CM, Wu GY. Human hepatocytes transplanted into genetically immunocompetent rats are susceptible to infection by hepatitis B virus in situ. J Viral Hepat 2001; 8:111-9. [PMID: 11264731 DOI: 10.1046/j.1365-2893.2001.00263.x] [Citation(s) in RCA: 19] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
Immune tolerance of human cells without generalized immunosuppression was created in groups of normal fetal rats at 17 days of gestation by inoculation ip with primary human hepatocytes in utero. One day after birth, suspensions of human hepatocytes were transplanted via intrasplenic injection and one week later groups of rats were inoculated with hepatitis B virus (HBV). Tolerized rats that were transplanted with human hepatocytes and subsequently infected with HBV produced hepatitis B surface antigen (HBsAg) in serum beginning on day 3. Levels rose fivefold and remained stable at 0.75 pg/ml through at least 60 days. Of cells that stained positive for human serum albumin, approximately 30% were found to be also positive for HBsAg by immunohistochemistry. Serum HBV DNA was detectable from 1 to 15 weeks postinfection. Finally, covalently closed circular DNA, reflecting HBV replication, was found in liver and serum. Controls that were tolerized and not transplanted, but inoculated with HBV, as well as untreated controls, had no evidence of HBV gene expression or replication under identical conditions. The data support the conclusion that primary human hepatocytes transplanted into genetically immunocompetent rodent hosts, survive and maintain sufficient differentiation to produce human serum albumin and be infected by HBV.
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Affiliation(s)
- C H Wu
- Division of Medicine, Department of Gastroenterology-Hepatology, University of Connecticut Health Center, Rm. AM-044, 263 Farmington Avenue, Farmington, CT 06030-1845, USA
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30
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Berger MA, Carleton M, Rhodes M, Sauder JM, Trop S, Dunbrack RL, Hugo P, Wiest DL. Identification of a novel pre-TCR isoform in which the accessibility of the TCR beta subunit is determined by occupancy of the 'missing' V domain of pre-T alpha. Int Immunol 2000; 12:1579-91. [PMID: 11058578 DOI: 10.1093/intimm/12.11.1579] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2023] Open
Abstract
We have identified a novel pre-TCR isoform that is structurally distinct from conventional pre-TCR complexes and whose TCR beta chains are inaccessible to anti-TCR beta antibodies. We term this pre-TCR isoform the MB (masked beta)-pre-TCR. Pre-T alpha (pT alpha) subunits of MB-pre-TCR complexes have a larger apparent mol. wt due to extensive modification with O:-linked carbohydrates; however, preventing addition of O-glycans does not restore antibody recognition of the TCR beta subunits of MB-pre-TCR complexes. Importantly, accessibility of TCR beta chains in MB-pre-TCR complexes is restored by filling in the 'missing' variable (V) domain of pT alpha with a V domain from TCR alpha. Moreover, the proportion of pre-TCR complexes in which the TCR beta subunits are accessible to anti-TCR beta antibody varies with the cellular context, suggesting that TCR beta accessibility is controlled by a trans-acting factor. The way in which this factor might control TCR beta accessibility as well as the physiologic relevance of TCR beta masking for pre-TCR function are discussed.
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MESH Headings
- Animals
- Carbohydrate Sequence
- Dimerization
- Gene Transfer Techniques
- Glycosylation
- Membrane Glycoproteins/biosynthesis
- Membrane Glycoproteins/deficiency
- Membrane Glycoproteins/genetics
- Membrane Glycoproteins/metabolism
- Mice
- Mice, Inbred C57BL
- Mice, Knockout
- Models, Molecular
- Molecular Sequence Data
- Protein Isoforms/biosynthesis
- Protein Isoforms/deficiency
- Protein Isoforms/genetics
- Protein Isoforms/isolation & purification
- Protein Structure, Tertiary/genetics
- Receptors, Antigen, T-Cell, alpha-beta/biosynthesis
- Receptors, Antigen, T-Cell, alpha-beta/deficiency
- Receptors, Antigen, T-Cell, alpha-beta/genetics
- Receptors, Antigen, T-Cell, alpha-beta/isolation & purification
- Thymus Gland/cytology
- Thymus Gland/immunology
- Thymus Gland/metabolism
- Tumor Cells, Cultured
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Affiliation(s)
- M A Berger
- Immunobiology Working Group, Fox Chase Cancer Center, Philadelphia, PA 19111, USA
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31
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OhYama T, Tsukumo S, Yajima N, Sakamaki K, Yonehara S. Reduction of thymocyte numbers in transgenic mice expressing viral FLICE-inhibitory protein in a Fas-independent manner. Microbiol Immunol 2000; 44:289-97. [PMID: 10832975 DOI: 10.1111/j.1348-0421.2000.tb02498.x] [Citation(s) in RCA: 19] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
A viral FLIP (FLICE/caspase-8-Inhibitory Protein), equine herpesvirus type 2 E8 protein, has been shown to inhibit Death receptor-induced apoptosis by suppressing the activation of FLICE/caspase-8. We generated transgenic mice specifically expressing E8 in thymocytes under the control of lck-proximal promoter. Although E8-expressing thymocytes were resistant to Fas-mediated apoptosis, the total number of thymocytes in 4-8-week-old E8 transgenic mice was more than 3-fold less than that in control littermates. This reduction was also observed in E8 transgenic mice with a Fas-/- background suggesting the reduction to be independent of Fas. The thymocytes of the transgenic mice, however, could similarly respond to CD3-mediated stimulation, indicating that the reduction of thymocyte numbers might be independent of T cell receptor complex-mediated stimulation. Thus, the Death receptor-mediated signaling pathway is too complex to be regarded as only an executor for apoptosis.
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Affiliation(s)
- T OhYama
- Institute for Virus Research, Kyoto University, Kyoto, Japan
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32
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Umemura M, Wajjwalku W, Upragarin N, Liu T, Nishimura H, Matsuguchi T, Nishiyama Y, Wilson GM, Yoshikai Y. Expression of mouse mammary tumor virus superantigen accelerates tumorigenicity of myeloma cells. J Virol 2000; 74:8226-33. [PMID: 10954519 PMCID: PMC116330 DOI: 10.1128/jvi.74.18.8226-8233.2000] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
To investigate whether superantigen (SAG) from endogenous mouse mammary tumor virus functions as an immunogenic or a tumorigenic factor in tumor development, the BALB/c myeloma cell line FO was transfected with the SAG gene from the 3' Mtv-50 long terminal repeat (LTR) open reading frame (ORF), the product of which was specific for Vbeta6. All five transfectants expressing Mtv-50 LTR ORF mRNA showed stimulatory activity for Vbeta6 T-cell hybridomas in vitro; this activity was inhibited by the addition of anti-Mtv-7 monoclonal antibody (MAb) or anti-major histocompatibility complex class II I-A(d) and I-E(d) MAb. All transfectants with the SAG gene grew more rapidly than did mock transfectants in BALB/c mice after subcutaneous inoculation, whereas all clones, including mock transfectants, grew equally well in athymic nude mice. A significant fraction of Vbeta6 T cells selectively expressed activation markers, including CD44(high), CD62L(low), and CD69(high), and produced large amounts of interleukin 5 (IL-5) and IL-6 in BALB/c mice inoculated with transfectants. These results suggested that the expression of viral SAG enhances the tumorigenicity of a myeloma cell line through the stimulation of SAG-reactive T cells.
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MESH Headings
- Animals
- Biomarkers, Tumor/biosynthesis
- CD4 Lymphocyte Count
- Flow Cytometry
- Interleukin-5/biosynthesis
- Interleukin-5/metabolism
- Interleukin-6/biosynthesis
- Interleukin-6/metabolism
- Leukemia, Myeloid
- Male
- Mammary Tumor Virus, Mouse/genetics
- Mice
- Mice, Inbred BALB C
- Mice, Nude
- Neoplasm Transplantation
- Receptors, Antigen, T-Cell, alpha-beta/immunology
- Receptors, Antigen, T-Cell, alpha-beta/metabolism
- Reverse Transcriptase Polymerase Chain Reaction
- Superantigens/genetics
- Superantigens/metabolism
- Superantigens/physiology
- Terminal Repeat Sequences
- Transfection
- Tumor Cells, Cultured
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Affiliation(s)
- M Umemura
- Laboratory of Host Defense, Research Institute for Disease Mechanism and Control, Nagoya University School of Medicine, Nagoya 466-8550, Japan
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33
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Abstract
Mouse mammary tumor virus (MMTV) superantigens (vSAgs) can undergo intercellular transfer in vivo and in vitro such that a vSAg can be presented to T cells by major histocompatibility complex (MHC) class II proteins on antigen-presenting cells (APCs) that do not express the superantigen. This process may allow T-cell activation to occur prior to viral infection. Consistent with these findings, vSAg produced by Chinese hamster ovary (CHO) cells was readily transferred to class II IE and IA (H-2(k) and H-2(d)) proteins on a B-cell lymphoma or mouse splenocytes. Fixed class II-expressing acceptor cells were used to demonstrate that the vSAg, but not the class II proteins, underwent intercellular transfer, indicating that vSAg binding to class II MHC could occur directly at the cell surface. Intercellular transfer also occurred efficiently to splenocytes from endogenous retrovirus-free mice, indicating that other proviral proteins were not involved. Presentation of vSAg7 produced by a class II-negative, furin protease-deficient CHO variant (FD11) was unsuccessful, indicating that proteolytic processing was a requisite event and that proteolytic activity could not be provided by an endoprotease on the acceptor APC. Furthermore, vSAg presentation was effected using cell-free supernatant from class II-negative, vSAg-positive cells, indicating that a soluble molecule, most likely produced by proteolytic processing, was sufficient to stimulate T cells. Because the membrane-proximal endoproteolytic cleavage site in the vSAg (residues 68 to 71) was not necessary for intercellular transfer, the data support the notion that the carboxy-terminal endoproteolytic cleavage product is an active vSAg moiety.
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Affiliation(s)
- M Reilly
- Wadsworth Center, New York State Department of Health, Albany, New York 12201-2002, USA
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34
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Huang CC, Coppola MA, Nguyen P, Carragher D, Rohl C, Flynn KJ, Altman JD, Blackman MA. Effect of Staphylococcus enterotoxin B on the concurrent CD8(+) T cell response to influenza virus infection. Cell Immunol 2000; 204:1-10. [PMID: 11006012 DOI: 10.1006/cimm.2000.1692] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Bacterial superantigens have potent in vivo effects. Respiratory viral infections are often associated with secondary bacterial infections, raising the likelihood of exposure to bacterial superantigens after the initiation of the anti-viral immune response. In this study, the general and V beta-specific effects of exposure to Staphylococcal enterotoxin B (SEB) during influenza virus infection on both the ongoing acute and the subsequent recall CD8(+) T cell responses were analyzed, using the well-characterized murine influenza model system and tetrameric MHC/peptide reagents to directly identify virus-specific T cells. The results show that although superantigen exposure during the primary viral infection caused delayed viral clearance, there was remarkably little effect of SEB on the magnitude or TCR repertoire of the ongoing cytolytic T cell response or on the recall response elicited by secondary viral infection. Thus, despite the well-characterized immunomodulatory effects of SEB, there was surprisingly little interference with concurrent anti-viral immunity.
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Affiliation(s)
- C C Huang
- Department of Immunology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA
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35
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Prell RA, Dearstyne E, Steppan LG, Vella AT, Kerkvliet NI. CTL hyporesponsiveness induced by 2,3,7, 8-tetrachlorodibenzo-p-dioxin: role of cytokines and apoptosis. Toxicol Appl Pharmacol 2000; 166:214-21. [PMID: 10906285 DOI: 10.1006/taap.2000.8971] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Studies have shown that blocking B7-mediated costimulation induces T cell tolerance via anergy or apoptosis. Provision of exogenous IL-2 can reverse or prevent the induction of tolerance. We have previously shown that TCDD-induced suppression of the CTL response to allogeneic P815 tumor cells is accompanied by decreased expression of CD86 (B7-2) as well as suppressed IL-2 and IFNgamma production. In the present studies, the role of IL-2 and IFNgamma and the analysis of inappropriate deletion of CD8(+) cells was examined. Administration of IL-2 on days 7-9 relative to the injection of P815 tumor cells dose-dependently increased the CTL activity and the generation of CD8(+) CTL effector cells in TCDD-treated mice. This increased CTL response was not due to recruitment of naive CTL precursors (CTLp), suggesting that a small pool of activated CTLp in TCDD-treated mice could respond to the IL-2. A much larger pool of activated CTLp in control mice was also expanded by IL-2 treatment. In contrast, treatment with IFNgamma during the same time period did not alter CTL activity in control or TCDD-treated mice. To address the possibility that insufficient IL-2 early in the response was responsible for the reduced pool of activated CTLp in TCDD-treated mice, IL-2 was administered on days 1-3 after P815 injection. However, not only did early treatment with IL-2 fail to restore the response in TCDD-treated mice, it suppressed the CTL response of non-TCDD-treated mice. To test whether exposure to TCDD induced apoptosis of activated CD8(+) T cells, phosphatidylserine (PS) expression was measured on various days after P815 tumor challenge. Surprisingly, the percentage of apoptotic CD8(+) T cells was significantly lower in TCDD-treated mice compared to controls throughout the allograft response. Similarly, exposure to TCDD failed to enhance peripheral deletion of Vbeta3(+)CD8(+) T cells after injection of the superantigen Staphylococcal enterotoxin A (SEA). Taken together, the data indicate that TCDD induces an early defect in CTLp activation that is not due to insufficient IL-2 or deletion of CD8(+) cells and may implicate a novel mechanism by which ligands of the Ah receptor disrupt CTL precursor activation.
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Affiliation(s)
- R A Prell
- Department of Environmental and Molecular Toxicology, Oregon State University, Corvallis, Oregon 97331, USA
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36
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Du YP, Deng CS, Lu DY, Huang MF, Guo SF, Hou W. Relation between HLA-DQA1 genes and genetic susceptibility to duodenal ulcer in Wuhan Hans. World J Gastroenterol 2000; 6:107-110. [PMID: 11819534 PMCID: PMC4723573 DOI: 10.3748/wjg.v6.i1.107] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To study the genetic susceptibility of HLA-DQA1 alleles to duodenal ulcer in Wuhan Hans. METHODS: Seventy patients with duodenal ulcer and fifty health y controls were examined for HLA-DQA1 genotypes. HLA-DQA1 typing was carried out by digesting the locus specific polymerase chain reaction amplified products with alleles specific restriction enzymes (PCR-RFLP), i.e. Apal I, Bsaj I, Hph I, Fok I, Mbo II and Mnl I.
RESULTS: The allele frequencies of DQA1*0301 and DQA1*0102 in patients with duodenal ulcer were significantly higher and lower respectivel y than those in healthy controls (0.40 vs 0.20, P = 0.003, Pc orret = 0.024) and (0.05 vs 0.14, P = 0.012, but P corret > 0.05), respectively.
CONCLUSION: DQA1*0301 is a susceptible gene for duodenal ulcer in Wuhan Hans, and there are immunogenetic differences in HLA-DQA1 locus between duodenal ulcer patients and healthy controls.
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37
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Maxwell JR, Weinberg A, Prell RA, Vella AT. Danger and OX40 receptor signaling synergize to enhance memory T cell survival by inhibiting peripheral deletion. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2000; 164:107-12. [PMID: 10605000 DOI: 10.4049/jimmunol.164.1.107] [Citation(s) in RCA: 178] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
This report defines a cell surface receptor (OX40) expressed on effector CD4 T cells, which when engaged in conjunction with a danger signal, rescues Ag-stimulated effector cells from activation-induced cell death in vivo. Specifically, three signals were necessary to promote optimal generation of long-lived CD4 T cell memory in vivo: Ag, a danger signal (LPS), and OX40 engagement. Mice treated with Ag or superantigen (SAg) alone produced very few SAg-specific T cells. OX40 ligation or LPS stimulation, enhanced SAg-driven clonal expansion and the survival of responding T cells. However, when SAg was administered with a danger signal at the time of OX40 ligation, a synergistic effect was observed which led to a 60-fold increase in the number of long-lived, Ag-specific CD4 memory T cells. These data lay the foundation for the provision of increased numbers of memory T cells which should enhance the efficacy of vaccine strategies for infectious diseases, or cancer, while also providing a potential target (OX40) to limit the number of auto-Ag-specific memory T cells in autoimmune disease.
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MESH Headings
- Adjuvants, Immunologic/physiology
- Animals
- Cell Differentiation/genetics
- Cell Differentiation/immunology
- Cell Survival/immunology
- Clonal Deletion/immunology
- Enterotoxins/pharmacology
- Epitopes, T-Lymphocyte/immunology
- Immunologic Memory/genetics
- Ligands
- Lymphocyte Activation
- Membrane Glycoproteins
- Mice
- Mice, Inbred BALB C
- Mice, Inbred C57BL
- Mice, Transgenic
- OX40 Ligand
- Receptors, OX40
- Receptors, Tumor Necrosis Factor/physiology
- Self Tolerance/physiology
- Signal Transduction/genetics
- Signal Transduction/immunology
- Superantigens/pharmacology
- T-Lymphocyte Subsets/cytology
- T-Lymphocyte Subsets/immunology
- T-Lymphocyte Subsets/metabolism
- Tumor Necrosis Factor Receptor Superfamily, Member 7/biosynthesis
- Tumor Necrosis Factor Receptor Superfamily, Member 7/immunology
- Tumor Necrosis Factor Receptor Superfamily, Member 7/metabolism
- Tumor Necrosis Factors
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Affiliation(s)
- J R Maxwell
- Department of Microbiology, Oregon State University, Corvallis 97331, USA
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38
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Sefrioui H, Billiau AD, Overbergh L, Rutgeerts O, Waer M. Influence of the additional injection of host-type bone marrow on the immune tolerance of minor antigen-mismatched chimeras: possible involvement of double-negative (natural killer) T cells. Transplantation 1999; 68:1560-7. [PMID: 10589955 DOI: 10.1097/00007890-199911270-00021] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
BACKGROUND It has previously been demonstrated that adding T cell-depleted (TCD) host bone marrow (BM) to an MHC-mismatched BM inoculum allows for induction of long-term stable chimeras without graft-versus-host disease (GVHD) even when non-TCD allogeneic BM was used. AIMS The present study was undertaken to investigate immune tolerance mechanisms in minor antigen-mismatched allogeneic BM chimeras when host-type BM was added to the BM inoculum. METHODS C3H (H2k, Thy 1.2, Mls 2a) recipients were conditioned with 9.5 gray (Gy) of total body irradiation. To exclude any interference with possible subclinical GVHD, 5x10(6) TCD AKR (H2k, Thy 1.1, Mls 1a) BM cells were injected with (syn + allo) or without (allo) 5x 10(6) TCD C3H BM cells. Chimerism, clonal deletion, and T lymphocyte subsets were scored using FACS and anti-mouse Thy, Vbeta6, Vbeta3, CD3, CD4, or CD8 monoclonal antibodies. The stability of tolerance was studied by investigating mixed lymphocyte reaction and cytotoxic T cell induction in chimeras after immunization with host, donor, or third-party (BALB/c) splenocytes. Breaking of chimerism was attempted by injecting nontolerant 40x10(6) host-type splenocytes 2 months after BM transplantation. Cytokines and Valpha14 mRNA were assayed using real time quantitative reverse transcriptase-polymerase chain reaction at 4 and 48 hr, respectively, after injection of nontolerant host-type splenocytes. RESULTS Both groups of mice became long-term stable mixed chimeras without any clinical sign of GVHD. Neither group was able to produce antihost nor antidonor cytotoxic T cells, even after immunization. The addition of syngeneic BM to the allogeneic inoculum reduced the overall level of allogeneic chimerism (from approximately 70% or approximately 85% in peripheral blood lymphocytes and spleen, respectively, in allo chimeras versus approximately 35% and approximately 60% in syn + allo chimeras). Moreover, it resulted in complete clonal deletion of both host-reactive (Vbeta3) and donor-reactive (Vbeta6) lymphocytes in syn + allo chimeras in contrast to in allo chimeras, in which only donor-reactive lymphocytes were completely deleted. After nontolerant C3H splenocyte injection, high levels of interleukin 2 mRNA were produced and chimerism decreased in syn + allo chimeras. In contrast, in allo chimeras, this maneuver was followed by the production of higher levels of interleukin 4 and interferon-gamma, and of Valpha14 mRNA, as well as by the proliferation of CD3+CD4-CD8- (double-negative) T cells and by an increase of donor chimerism. CONCLUSION The addition of host-type BM to the allogeneic inoculum has an influence on the level of chimerism, the extent of clonal deletion, and the reaction of chimeras after the injection of nontolerant host-type splenocytes. In the latter phenomenon, cytokine production and proliferation of Valpha14+ CD3+CD4-CD8- (double-negative, natural killer T) lymphocytes may be involved.
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Affiliation(s)
- H Sefrioui
- Laboratory of Experimental Transplantation, University of Leuven, Belgium
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39
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Boubou MI, Collette A, Voegtlé D, Mazier D, Cazenave PA, Pied S. T cell response in malaria pathogenesis: selective increase in T cells carrying the TCR V(beta)8 during experimental cerebral malaria. Int Immunol 1999; 11:1553-62. [PMID: 10464176 DOI: 10.1093/intimm/11.9.1553] [Citation(s) in RCA: 54] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/14/2022] Open
Abstract
To characterize the T cells involved in the pathogenesis of cerebral malaria (CM) induced by infection with Plasmodium berghei ANKA clone 1.49L (PbA 1.49L), the occurrence of the disease was assessed in mice lacking T cells of either the alphabeta or gammadelta lineage (TCRalphabeta(-/-) or TCRgammadelta(-/-)). TCRgammadelta(-/-) mice were susceptible to CM, whereas all TCRalphabeta(-/-) mice were resistant, suggesting that T cells of the alphabeta lineage are important in the genesis of CM. The repertoire of TCR V(beta) segment gene expression was examined by flow cytometry in B10.D2 mice, a strain highly susceptible to CM induced by infection with PbA 1.49L. In these mice, CM was associated with an increase of T cells bearing the V(beta)8.1, 2 segments in the peripheral blood lymphocytes. Most V(beta)8.1, 2(+) T cells from peripheral blood lymphocytes of the mice that developed CM belonged to the CD8 subset, and exhibited the CD69(+), CD44(high) and CD62L(low) phenotype surface markers. The link between the increase in V(beta)8.1, 2(+) T cells and the neuropathological consequences of PbA infection was strengthened by the observation that the occurrence of CM was significantly reduced in mice treated with KJ16 antibodies against the V(beta)8.1 and V(beta)8.2 chains, and in mice rendered deficient in V(beta)8.1(+) T cells by a mouse mammary tumor virus superantigen.
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MESH Headings
- Animals
- CD4 Antigens/genetics
- Genes, T-Cell Receptor/genetics
- Lymphocyte Count
- Malaria, Cerebral/immunology
- Mice
- Mice, Congenic
- Mice, Inbred BALB C
- Mice, Inbred C57BL
- Mice, Inbred DBA
- Mice, Knockout
- Plasmodium berghei
- Receptors, Antigen, T-Cell/genetics
- Receptors, Antigen, T-Cell/immunology
- T-Lymphocyte Subsets/immunology
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Affiliation(s)
- M I Boubou
- INSERM U511, Immunobiologie Cellulaire et Moléculaire des Infections Parasitaires,CHU Pitié-Salpêtrière, 75643 Paris Cedex 13, France
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40
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Kariyone A, Higuchi K, Yamamoto S, Nagasaka-Kametaka A, Harada M, Takahashi A, Harada N, Ogasawara K, Takatsu K. Identification of amino acid residues of the T-cell epitope of Mycobacterium tuberculosis alpha antigen critical for Vbeta11(+) Th1 cells. Infect Immun 1999; 67:4312-9. [PMID: 10456868 PMCID: PMC96746 DOI: 10.1128/iai.67.9.4312-4319.1999] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Stimulation of Mycobacterium tuberculosis-primed lymph node cells from C57BL/6 mice with alpha antigen (also known as antigen 85B and MPT59) induced cell proliferation, production of interleukin 2 and gamma interferon, and expansion of Vbeta11(+) CD4(+) T cells in conjunction with antigen-presenting cells in an I-A(b)-restricted manner. Using a series of 15-amino-acid peptides that overlapped each other by 5 amino acids and spanned the mature alpha antigen, we identified the antigenic epitope for alpha antigen-specific Vbeta11(+) Th1 cells. That peptide (peptide-25), which corresponds to amino acid residues 240 to 254 of alpha antigen, contains a motif that is conserved in I-A(b) and requires processing by antigen-presenting cells. Using peptide-25-reactive Vbeta11(+) T-cell clones and substituted peptide-25 mutants, we determined which amino acid residues within peptide-25 were critical for T-cell receptor (TCR) recognition. Our results showed that the amino acid residues at positions 245, 246, 248, 250, and 251 are important for recognition of TCRVbeta11 and that residues at positions 244, 247, 249, and 252 are I-A(b) contact residues. We also observed that active immunization of C57BL/6 mice with peptide-25 can lead to decreased bacterial load in the lungs of M. tuberculosis H37Rv-infected mice. These results should provide us with a useful tool for delineating the regulation of Vbeta11(+) Th1-cell development during M. tuberculosis infection and for developing a vaccine inducing a Th1-dominant immune response.
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Affiliation(s)
- A Kariyone
- Department of Immunology, Institute of Medical Science, University of Tokyo, Minato-ku, Japan
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Koh WP, Chan E, Scott K, McCaughan G, France M, Fazekas de St. Groth B. TCR-Mediated Involvement of CD4+ Transgenic T Cells in Spontaneous Inflammatory Bowel Disease in Lymphopenic Mice. THE JOURNAL OF IMMUNOLOGY 1999. [DOI: 10.4049/jimmunol.162.12.7208] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
Abstract
Spontaneous colitis resembling ulcerative colitis developed in 3 of 10 independent TCR transgenic (Tg) mouse lines maintained under specific pathogen-free conditions. All three susceptible lines were CD4 lymphopenic, whereas resistant lines had normal numbers of CD4+ T cells. Thus, cytochrome c-specific 5C.C7 TCR Tg mice developed colitis only when crossed onto a SCID- or Rag-1-deficient background. A second line of lymphopenic cytochrome c-specific Tg mice bearing the AND TCR also developed colitis. In both cases, CD4+ T cells expressing the Tg-encoded TCR were preferentially activated in inflamed colons compared with lymph nodes or spleens. In contrast, Tg+CD4+ T cells remained quiescent in both inflamed and unaffected colons in another line of susceptible Tg mice carrying a TCR specific for myelin basic protein, suggesting a fortuitous cross-reactivity of the IEk-restricted cytochrome c-reactive AND and 5C.C7 TCRs with an Ag present in the gut. The percentage of CD4+ T cells expressing only endogenous TCR α-chains was increased consistently in inflamed colons in AND as well as 5C.C7 Rag-1−/− TCR Tg mice, suggesting that polyclonal CD4+ T cells were also involved in the pathogenesis of spontaneous colitis. Moreover, our data indicate that some α-chain rearrangement was still occurring in TCR Tg mice on a Rag-1−/− background, since activated CD4+ T cells expressing endogenously rearranged α-chains paired with the Tg-encoded β-chain were detected consistently in the colons of such mice.
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Affiliation(s)
- Woon-Puay Koh
- *Centenary Institute of Cancer Medicine and Cell Biology, Newtown, Australia; and
| | - Elsie Chan
- *Centenary Institute of Cancer Medicine and Cell Biology, Newtown, Australia; and
| | - Kate Scott
- *Centenary Institute of Cancer Medicine and Cell Biology, Newtown, Australia; and
| | - Geoffrey McCaughan
- *Centenary Institute of Cancer Medicine and Cell Biology, Newtown, Australia; and
| | - Malcolm France
- †Department of Veterinary Pathology, University of Sydney, Sydney, Australia
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Rovira P, Buckle M, Abastado JP, Peumans WJ, Truffa-Bachi P. Major histocompatibility class I molecules present Urtica dioica agglutinin, a superantigen of vegetal origin, to T lymphocytes. Eur J Immunol 1999; 29:1571-80. [PMID: 10359111 DOI: 10.1002/(sici)1521-4141(199905)29:05<1571::aid-immu1571>3.0.co;2-x] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/07/2022]
Abstract
The Urtica dioica agglutinin (UDA) shares with the superantigens the property of activating T cell subsets bearing particular Vbeta segments of the TCR. However, UDA is a lectin capable of binding to many glycoproteins on cell membranes. The implication of MHC versus other glycoproteins in UDA presentation was presently studied. Using mutant mice lacking MHC class I (MHC-I), MHC class II (MHC-II) or both MHC antigens, we provided evidence that MHC-I and MHC-II molecules serve as UDA receptors. Presentation by either one of these molecules ensured similar T cell responses and co-stimulatory signals were mandatory for optimal T cell activation and proliferation both in MHC-I and MHC-II contexts. Remarkably, in the absence of MHC molecules, UDA could not be efficiently presented to T cells by other glycosylated proteins. Surface plasmon resonance studies were used to confirm the binding of UDA to MHC-I molecules using a fusion protein consisting of MHC-I domains and beta2-microglobulin. The results indicated that the interaction between UDA and MHC-I molecules implicated lectin-binding site(s) of UDA. Taken together, our data demonstrate that, in addition to MHC-II antigens, MHC-I molecules serve as an alternative ligand for UDA.
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Affiliation(s)
- P Rovira
- Unité d'Immunophysiologie Moléculaire, Institut Pasteur, Paris, France
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Dyson PJ, Elliott JI. Chronic deletion, escape from deletion and activation of mouse mammary tumor virus superantigen-reactive T cells in C57BL/10 mice. Eur J Immunol 1999; 29:1456-66. [PMID: 10359099 DOI: 10.1002/(sici)1521-4141(199905)29:05<1456::aid-immu1456>3.0.co;2-d] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Though C57BL/10 mice express the mouse mammary tumor virus superantigens (sag) encoded by Mtv-8 and Mtv-9, it has been thought that these sag do not bind to the MHC class II molecule H2-Ab and consequently do not affect the T cell repertoire. However, we show that cells bearing TCR Vbeta chains specific for Mtv-8 and -9 sag are chronically deleted in C57BL/10 mice. Thymocytes and peripheral T cells escaping deletion by Mtv sag display a small reduction in the level of cell surface CD4. T cells escaping thymic deletion respond variably to endogenous Mtv sag with some, but not all, reactive populations appearing overrepresented in the activated/memory subset. The data suggest that in normal mice fine modulation of coreceptor expression levels may be a common way by which thymocytes escape elimination, that systems utilizing potentially Mtv sag-reactive TCR on a C57BL background may be inappropriate for the measurement of the affinity of TCR/MHC/peptide interactions required in thymic selection, and that detection of the activity of human sag may be aided by analysis of CD4 levels and activation markers on T cells in conjunction with studies of the frequency of cells bearing specific TCRVbeta chains.
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Affiliation(s)
- P J Dyson
- Transplantation Biology Group, MRC Clinical Sciences Centre, Imperial College School of Medicine, Hammersmith Hospital, London, GB
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Takahashi C, Mittler RS, Vella AT. Cutting Edge: 4-1BB Is a Bona Fide CD8 T Cell Survival Signal. THE JOURNAL OF IMMUNOLOGY 1999. [DOI: 10.4049/jimmunol.162.9.5037] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
Abstract
After recognition of Ag/MHC and ligation of a costimulatory molecule, resting T cells will clonally expand and then delete to very low levels. Previously, it was shown that deletion can be prevented by coinjection of cytokines or proinflammatory agents such as adjuvants. Here, we demonstrate that ligation of 4-1BB blocks deletion of superantigen-activated T cells in the absence of adjuvant or additional cytokine treatment. Nearly 10 times as many staphylococcal enterotoxin A-specific T cells were detected in the spleens of mice injected 21 days previously with staphylococcal enterotoxin A and an agonist anti-4-1BB Ab compared with mice given staphylococcal enterotoxin A and a control IgG. Even though both CD4- and CD8-activated T cells expressed 4-1BB, a higher proportion of CD8 T cells were rescued compared CD4 T cells. These data suggest that although 4-1BB provides costimulation, it may also promote long-term T cell survival.
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Affiliation(s)
- Chikara Takahashi
- *Department of Microbiology, Oregon State University, Corvallis OR 97331; and
| | - Robert S. Mittler
- †Department of Immunology and Inflammation, Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, NJ 08540
| | - Anthony T. Vella
- *Department of Microbiology, Oregon State University, Corvallis OR 97331; and
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Maxwell JR, Campbell JD, Kim CH, Vella AT. CD40 Activation Boosts T Cell Immunity In Vivo by Enhancing T Cell Clonal Expansion and Delaying Peripheral T Cell Deletion. THE JOURNAL OF IMMUNOLOGY 1999. [DOI: 10.4049/jimmunol.162.4.2024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Abstract
Abstract
In this report we show that activation of APC with an agonist anti-CD40 mAb profoundly alters the behavior of CD4 T cells in vivo. Stimulation of mice with anti-CD40 2 days before, but not 1 day after, administration of superantigen (SAg) enhanced CD4 and CD8 T cell clonal expansion by approximately threefold. Further, CD40 activation also delayed peripheral T cell deletion after activation. Dying, activated T cells were quantitated by detecting extracellular phosphatidylserine with concomitant staining for SAg-reactive T cells using a TCR Vβ-specific mAb. Upon close examination, it was shown that CD40 activation delayed the death of the activated T cells. Additionally, it was found that enhanced survival of CD4 T cells was equally dependent on APC expression of B7-1 and B7-2. This is in contrast to CD8 T cells, which did not depend as much on B7-1 as B7-2. Thus, CD40 activation indirectly promotes T cell growth and delays the death of SAg-stimulated CD4 T cells in vivo. These data suggest that one way CD40 activation promotes a more robust immune response is by indirectly increasing the production of effector T cells and by keeping them alive for longer periods of time.
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Affiliation(s)
- Joseph R. Maxwell
- Department of Microbiology, Oregon State University, Corvallis, OR 97331
| | - Jeff D. Campbell
- Department of Microbiology, Oregon State University, Corvallis, OR 97331
| | - Carol H. Kim
- Department of Microbiology, Oregon State University, Corvallis, OR 97331
| | - Anthony T. Vella
- Department of Microbiology, Oregon State University, Corvallis, OR 97331
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Itoh Y, Hemmer B, Martin R, Germain RN. Serial TCR Engagement and Down-Modulation by Peptide:MHC Molecule Ligands: Relationship to the Quality of Individual TCR Signaling Events. THE JOURNAL OF IMMUNOLOGY 1999. [DOI: 10.4049/jimmunol.162.4.2073] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Abstract
Abstract
In the present study, we examined the relationships among quantitative aspects of TCR engagement as measured by receptor down-modulation, functional responses, and biochemical signaling events using both mouse and human T cell clones. For T cells from both species, ligands that are more potent in inducing functional responses promote TCR down-modulation more efficiently than weaker ligands. At low ligand density, the number of down-modulated TCR exceeds the number of available ligands by as much as 80–100:1 in the optimal human case, confirming the previous description of serial ligand engagement of TCR (Valitutti, et al. 1995. Nature 375:148–151). A previously unappreciated relationship involving TCR down-modulation, the pattern of proximal TCR signaling, and the extent of serial engagement was revealed by analyzing different ligands for the same TCR. Functionally, more potent ligands induce a higher proportion of fully tyrosine phosphorylated ζ-chains and a greater amount of phosphorylated ZAP-70 than less potent ligands, and the number of TCR down-modulated per available ligand is higher with ligands showing this full agonist-like pattern. The large number of receptors showing partial ζ phosphorylation following exposure to weak ligands indicates that the true extent of TCR engagement and signaling, and thus the amount of sequential engagement, is underestimated by measurement of TCR down-modulation alone, which depends on full receptor activation. These data provide new insight into T cell activation by revealing a clear relationship among intrinsic ligand quality, signal amplification by serial engagement, functional T cell responses, and observable TCR clearance from the cell surface.
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Affiliation(s)
- Yasushi Itoh
- *Lymphocyte Biology Section, Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, and
| | - Bernhard Hemmer
- †Cellular Immunology Section, Neuroimmunology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892
| | - Roland Martin
- †Cellular Immunology Section, Neuroimmunology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892
| | - Ronald N. Germain
- *Lymphocyte Biology Section, Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, and
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Sano T, Yamamoto K, Fukui Y, Sasazuki T. Spontaneous clustering of Thy-1 antigens on CD4+ CD8+ thymocytes lacking TCR engagement by MHC/peptide complexes. Eur J Immunol 1999; 29:403-12. [PMID: 10064055 DOI: 10.1002/(sici)1521-4141(199902)29:02<403::aid-immu403>3.0.co;2-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
While much is known concerning CD4+ CD8+ thymocytes positively or negatively selected through interaction of their TCR with self peptides bound to self-MHC molecules, little is known of the majority of CD4+ CD8+ thymocytes lacking this interaction. We developed a monoclonal antibody (mAb) 1D11, the ligand of which (1D11-L) is expressed on 60-70% of CD4+ CD8+ thymocytes but not on other subsets of thymocytes and peripheral T cells. 1D11-L expression on CD4+ CD8+ thymocytes reversely correlates with their TCR engagement, in vitro and in vivo. In addition, 1D11-L+ CD4+ CD8+ thymocytes were more susceptible than 1D11-L- CD4+ CD8- thymocytes to apoptosis. We also found that T lineage cells other than CD4+ CD8+ thymocytes and a Thy-1-expressing fibroblast cell line became positive for 1D11-L by cross-linking their Thy-1 antigens with anti-Thy-1 mAb but not with their Fab fragment, suggesting that 1D11 recognizes multimerized Thy-1 antigens. Confocal laser scanning microscopy revealed that Thy-1 antigens as well as 1D11-L are clustered on some CD4+ CD8+ thymocytes but not on the other subsets of thymocytes. Taken together, we suggest that clustering of Thy-1 antigens spontaneously and specifically occurs on CD4+ CD8+ thymocytes lacking TCR engagement by MHC/peptide complexes.
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Affiliation(s)
- T Sano
- Department of Genetics, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan
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Girgis L, Davis MM, Fazekas de St Groth B. The avidity spectrum of T cell receptor interactions accounts for T cell anergy in a double transgenic model. J Exp Med 1999; 189:265-78. [PMID: 9892609 PMCID: PMC2192997 DOI: 10.1084/jem.189.2.265] [Citation(s) in RCA: 39] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/1998] [Revised: 10/27/1998] [Indexed: 11/16/2022] Open
Abstract
The mechanism of self-tolerance in the CD4(+) T cell compartment was examined in a double transgenic (Tg) model in which T cell receptor (TCR)-alpha/beta Tg mice with specificity for the COOH-terminal peptide of moth cytochrome c in association with I-Ek were crossed with antigen Tg mice. Partial deletion of cytochrome-reactive T cells in the thymus allowed some self-specific CD4(+) T cells to be selected into the peripheral T cell pool. Upon restimulation with peptide in vitro, these cells upregulated interleukin (IL)-2 receptor but showed substantially lower cytokine production and proliferation than cells from TCR Tg controls. Proliferation and cytokine production were restored to control levels by addition of saturating concentrations of IL-2, consistent with the original in vitro definition of T cell anergy. However, the response of double Tg cells to superantigen stimulation in the absence of exogenous IL-2 was indistinguishable from that of TCR Tg controls, indicating that these self-reactive cells were not intrinsically hyporesponsive. Measurement of surface expression of Tg-encoded TCR alpha and beta chains revealed that cells from double Tg mice expressed the same amount of TCR-beta as cells from TCR Tg controls, but only 50% of TCR-alpha, implying expression of more than one alpha chain. Naive CD4(+) T cells expressing both Tg-encoded and endogenous alpha chains also manifested an anergic phenotype upon primary stimulation with cytochrome c in vitro, suggesting that low avidity for antigen can produce an anergic phenotype in naive cells. The carboxyfluorescein diacetate succinimidyl ester cell division profiles in response to titered peptide +/- IL-2 indicated that expression of IL-2 receptor correlated with peptide concentration but not TCR level, whereas IL-2 production was profoundly affected by the twofold decrease in specific TCR expression. Addition of exogenous IL-2 recruited double Tg cells into division, resulting in a pattern of cell division indistinguishable from that of controls. Thus, in this experimental model, cells expressing more than one alpha chain escaped negative selection to a soluble self-protein in the thymus and had an anergic phenotype indistinguishable from that of low avidity naive cells. The data are consistent with the notion that avidity-mediated selection for self-reactivity in the thymus may lead to the appearance of anergy within the peripheral, self-reactive T cell repertoire, without invoking the induction of hyporesponsiveness to TCR-mediated signals.
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Affiliation(s)
- L Girgis
- Centenary Institute of Cancer Medicine and Cell Biology, Newtown, Sydney, New South Wales 2042, Australia
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49
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Li Z, Wu W, Kemp O, Stephen M, Manolios N. The interchain disulfide linkage of T-cell antigen receptor-alpha and -beta chains is a prerequisite for T-cell activation. Cell Immunol 1998; 190:101-11. [PMID: 9878111 DOI: 10.1006/cimm.1998.1383] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Complementary DNAs encoding the T-cell antigen receptor (TCR)-alpha and mutant TCR-beta chains, lacking the interchain disulfide bond-related cysteine, were introduced into a TCR-alpha and -beta protein-deficient T-cell line. TCR-alpha and the mutant TCR-beta chains assembled with the CD3-epsilon, -gamma, -delta, and -zeta subunits and were efficiently transported to the cell surface; however, the hybrid TCR molecules exhibited a diminished response to T-cell activation by major histocompatibility complex-bound antigen, superantigen, and TCR cross-linking. These results suggest that the interchain disulfide bond between the TCR clonotypic chains is not required for TCR assembly and cell surface expression, but it plays an important role in maintaining the functional integrity of the TCR complex.
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Affiliation(s)
- Z Li
- Department of Rheumatology, Royal North Shore Hospital, New South Wales, 2065, Australia
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50
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Abstract
Co-culture of purified T and B cells obtained from cytochrome c-specific TCR- and hen egg lysozyme (HEL)-specific Ig-transgenic mice was used to examine the role of B cell receptor (BCR) ligation and TCR affinity on the efficiency of T-B cell collaboration. The results showed that BCR ligation of naive B cells with HEL was not required for effective presentation of high-affinity antigen to T cells, although it did enhance activation and division of both T and B cells. Anergic B cells were also effective at presentation of high-affinity antigen and proliferated more than naive B cells in response to T cell help, due to prior exposure to antigen in vivo. Despite the fact that induction of CD86 on anergic B cells following BCR ligation was suboptimal, these cells supported T cell activation and survival in culture as efficiently as naive B cells exposed to HEL. In contrast, when the low-affinity antigen mls-3a served as the T cell stimulus, BCR ligation was essential to elicit a detectable T cell response. Thus the in vitro model demonstrates that co-stimulation is not an absolute requirement for effective antigen presentation and delivery of T cell help to B cells. Rather, the cooperative effects of BCR ligation and TCR affinity determine the relative requirement for co-stimulation.
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Affiliation(s)
- M C Cook
- Centenary Institute of Cancer Medicine and Cell Biology, Sydney, Australia
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