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Qin J, Zhang Z, Cui H, Yang J, Liu A. Biological characteristics and immune responses of NK Cells in commonly used experimental mouse models. Front Immunol 2024; 15:1478323. [PMID: 39628473 PMCID: PMC11611892 DOI: 10.3389/fimmu.2024.1478323] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2024] [Accepted: 11/04/2024] [Indexed: 12/06/2024] Open
Abstract
The biology of natural killer (NK) cells in commonly used mouse models is discussed in this review, along with their crucial function in a variety of immunological responses. It has been demonstrated that the formation, maturation, subtype variety, and immunological recognition mechanisms of NK cells from various mice strains exhibit notable differences. These variations shed light on the intricacy of NK cell function and offer crucial information regarding their possible uses in treating human illnesses. The application of flow cytometry in mouse NK cell research is also covered in the article. Improved knowledge of the biology of NK cells across species may facilitate the development of new NK cell-based therapeutic approaches.
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Affiliation(s)
- Jingwen Qin
- Department of Gastroenterology and Respiratory Internal Medicine & Endoscopy Center, Guangxi Medical University Cancer Hospital, Nanning, China
| | - Zhaokai Zhang
- Department of General Surgery II, Cenxi People’s Hospital, Wuzhou, Guangxi, China
| | - Haopeng Cui
- Department of Gastroenterology and Respiratory Internal Medicine & Endoscopy Center, Guangxi Medical University Cancer Hospital, Nanning, China
| | - Jinhua Yang
- Department of Gastroenterology and Respiratory Internal Medicine & Endoscopy Center, Guangxi Medical University Cancer Hospital, Nanning, China
| | - Aiqun Liu
- Department of Gastroenterology and Respiratory Internal Medicine & Endoscopy Center, Guangxi Medical University Cancer Hospital, Nanning, China
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2
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Wlodarczyk M, Torun A, Zerrouqi A, Pyrzynska B. NK Cell Degranulation Triggered by Rituximab Identifies Potential Markers of Subpopulations with Enhanced Cytotoxicity toward Malignant B Cells. Int J Mol Sci 2024; 25:8980. [PMID: 39201666 PMCID: PMC11354239 DOI: 10.3390/ijms25168980] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2024] [Revised: 08/12/2024] [Accepted: 08/16/2024] [Indexed: 09/03/2024] Open
Abstract
A promising strategy in cancer immunotherapy is to restore or enhance the cytotoxicity of NK cells, among others, by activating the mechanism of antibody-dependent cellular cytotoxicity (ADCC). Monoclonal antibodies targeting tumor antigens, such as rituximab (targeting CD20), induce NK cell-mediated ADCC and have been used to treat B cell malignancies, such as non-Hodgkin lymphoma, but not always successfully. The aim of this study was to analyze the gene expression profile of the NK cells involved in the cytolytic response stimulated by rituximab. NK cells were co-cultured with rituximab-opsonized Raji cells. Sorting into responder and non-responder groups was based on the presence of CD107a, which is a degranulation marker. RNA-seq results showed that the KIT and TNFSF4 genes were strongly down-regulated in the degranulating population of NK cells (responders); this was further confirmed by qRT-PCR. Both genes encode surface proteins with cellular signaling abilities, namely c-KIT and the OX40 ligand. Consistent with our findings, c-KIT was previously reported to correlate inversely with cytokine production by activated NK cells. The significance of these findings for cancer immunotherapy seems essential, as the pharmacological inhibition of c-KIT and OX40L, or gene ablation, could be further tested for the enhancement of the anti-tumor activity of NK cells in response to rituximab.
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Affiliation(s)
- Marta Wlodarczyk
- Chair and Department of Biochemistry, Faculty of Medicine, Medical University of Warsaw, 02-091 Warsaw, Poland; (M.W.); (A.T.); (A.Z.)
- Department of Biochemistry and Pharmacogenomics, Faculty of Pharmacy, Medical University of Warsaw, 02-097 Warsaw, Poland
- Centre for Preclinical Research, Medical University of Warsaw, 02-097 Warsaw, Poland
| | - Anna Torun
- Chair and Department of Biochemistry, Faculty of Medicine, Medical University of Warsaw, 02-091 Warsaw, Poland; (M.W.); (A.T.); (A.Z.)
- Institute of Mother and Child, 01-211 Warsaw, Poland
| | - Abdessamad Zerrouqi
- Chair and Department of Biochemistry, Faculty of Medicine, Medical University of Warsaw, 02-091 Warsaw, Poland; (M.W.); (A.T.); (A.Z.)
- Centre for Preclinical Research, Medical University of Warsaw, 02-097 Warsaw, Poland
| | - Beata Pyrzynska
- Chair and Department of Biochemistry, Faculty of Medicine, Medical University of Warsaw, 02-091 Warsaw, Poland; (M.W.); (A.T.); (A.Z.)
- Centre for Preclinical Research, Medical University of Warsaw, 02-097 Warsaw, Poland
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3
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Hamdan TA. The Multifaceted Roles of NK Cells in the Context of Murine Cytomegalovirus and Lymphocytic Choriomeningitis Virus Infections. Immune Netw 2024; 24:e29. [PMID: 39246620 PMCID: PMC11377952 DOI: 10.4110/in.2024.24.e29] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2024] [Revised: 05/30/2024] [Accepted: 06/03/2024] [Indexed: 09/10/2024] Open
Abstract
NK cells belong to innate lymphoid cells and able to eliminate infected cells and tumor cells. NK cells play a valuable role in controlling viral infections. Also, they have the potential to shape the adaptive immunity via a unique crosstalk with the different immune cells. Murine models are important tools for delineating the immunological phenomena in viral infection. To decipher the immunological virus-host interactions, two major infection models are being investigated in mice regarding NK cell-mediated recognition: murine cytomegalovirus (MCMV) and lymphocytic choriomeningitis virus (LCMV). In this review, we recapitulate recent findings regarding the multifaceted role of NK cells in controlling LCMV and MCMV infections and outline the exquisite interplay between NK cells and other immune cells in these two settings. Considering that, infections with MCMV and LCMV recapitulates many physiopathological characteristics of human cytomegalovirus infection and chronic virus infections respectively, this study will extend our understanding of NK cells biology in interactions between the virus and its natural host.
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Affiliation(s)
- Thamer A Hamdan
- Department of Basic Dental Sciences, Faculty of Dentistry, Al-Ahliyya Amman University, Amman 19328, Jordan
- Department of Medical Laboratory Sciences, Faculty of Allied Medical Sciences, Al-Ahliyya Amman University, Amman 19328, Jordan
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Lerner EC, Woroniecka KI, D'Anniballe VM, Wilkinson DS, Mohan AA, Lorrey SJ, Waibl-Polania J, Wachsmuth LP, Miggelbrink AM, Jackson JD, Cui X, Raj JA, Tomaszewski WH, Cook SL, Sampson JH, Patel AP, Khasraw M, Gunn MD, Fecci PE. CD8 + T cells maintain killing of MHC-I-negative tumor cells through the NKG2D-NKG2DL axis. NATURE CANCER 2023; 4:1258-1272. [PMID: 37537301 PMCID: PMC10518253 DOI: 10.1038/s43018-023-00600-4] [Citation(s) in RCA: 45] [Impact Index Per Article: 22.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/08/2022] [Accepted: 06/20/2023] [Indexed: 08/05/2023]
Abstract
The accepted paradigm for both cellular and anti-tumor immunity relies upon tumor cell killing by CD8+ T cells recognizing cognate antigens presented in the context of target cell major histocompatibility complex (MHC) class I (MHC-I) molecules. Likewise, a classically described mechanism of tumor immune escape is tumor MHC-I downregulation. Here, we report that CD8+ T cells maintain the capacity to kill tumor cells that are entirely devoid of MHC-I expression. This capacity proves to be dependent instead on interactions between T cell natural killer group 2D (NKG2D) and tumor NKG2D ligands (NKG2DLs), the latter of which are highly expressed on MHC-loss variants. Necessarily, tumor cell killing in these instances is antigen independent, although prior T cell antigen-specific activation is required and can be furnished by myeloid cells or even neighboring MHC-replete tumor cells. In this manner, adaptive priming can beget innate killing. These mechanisms are active in vivo in mice as well as in vitro in human tumor systems and are obviated by NKG2D knockout or blockade. These studies challenge the long-advanced notion that downregulation of MHC-I is a viable means of tumor immune escape and instead identify the NKG2D-NKG2DL axis as a therapeutic target for enhancing T cell-dependent anti-tumor immunity against MHC-loss variants.
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Affiliation(s)
- Emily C Lerner
- Duke University School of Medicine, Durham, NC, USA
- Department of Biomedical Engineering, Duke University, Durham, NC, USA
| | | | | | - Daniel S Wilkinson
- Preston Robert Tisch Brain Tumor Center, Duke University Medical Center, Durham, NC, USA
- Department of Neurosurgery, Duke University Medical Center, Durham, NC, USA
| | - Aditya A Mohan
- Department of Neurosurgery, Duke University Medical Center, Durham, NC, USA
| | - Selena J Lorrey
- Department of Immunology, Duke University Medical Center, Durham, NC, USA
| | | | - Lucas P Wachsmuth
- Duke University School of Medicine, Durham, NC, USA
- Department of Pathology, Duke University Medical Center, Durham, NC, USA
| | | | - Joshua D Jackson
- Department of Neurosurgery, Duke University Medical Center, Durham, NC, USA
| | - Xiuyu Cui
- Department of Neurosurgery, Duke University Medical Center, Durham, NC, USA
| | - Jude A Raj
- Duke University School of Medicine, Durham, NC, USA
| | | | - Sarah L Cook
- Preston Robert Tisch Brain Tumor Center, Duke University Medical Center, Durham, NC, USA
- Department of Neurosurgery, Duke University Medical Center, Durham, NC, USA
| | - John H Sampson
- Preston Robert Tisch Brain Tumor Center, Duke University Medical Center, Durham, NC, USA
- Department of Neurosurgery, Duke University Medical Center, Durham, NC, USA
| | - Anoop P Patel
- Preston Robert Tisch Brain Tumor Center, Duke University Medical Center, Durham, NC, USA
- Department of Neurosurgery, Duke University Medical Center, Durham, NC, USA
- Center for Advanced Genomic Technologies, Duke University, Durham, NC, USA
| | - Mustafa Khasraw
- Preston Robert Tisch Brain Tumor Center, Duke University Medical Center, Durham, NC, USA
| | - Michael D Gunn
- Department of Immunology, Duke University Medical Center, Durham, NC, USA
- Department of Medicine, Duke University Medical Center, Durham, NC, USA
| | - Peter E Fecci
- Preston Robert Tisch Brain Tumor Center, Duke University Medical Center, Durham, NC, USA.
- Department of Neurosurgery, Duke University Medical Center, Durham, NC, USA.
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David C, Ruck T, Rolfes L, Mencl S, Kraft P, Schuhmann MK, Schroeter CB, Jansen R, Langhauser F, Mausberg AK, Fender AC, Meuth SG, Kleinschnitz C. Impact of NKG2D Signaling on Natural Killer and T-Cell Function in Cerebral Ischemia. J Am Heart Assoc 2023:e029529. [PMID: 37301761 DOI: 10.1161/jaha.122.029529] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/01/2023] [Accepted: 04/04/2023] [Indexed: 06/12/2023]
Abstract
Background Typically defined as a thromboinflammatory disease, ischemic stroke features early and delayed inflammatory responses, which determine the extent of ischemia-related brain damage. T and natural killer cells have been implicated in neuronal cytotoxicity and inflammation, but the precise mechanisms of immune cell-mediated stroke progression remain poorly understood. The activating immunoreceptor NKG2D is expressed on both natural killer and T cells and may be critically involved. Methods and Results An anti-NKG2D blocking antibody alleviated stroke outcome in terms of infarct volume and functional deficits, coinciding with reduced immune cell infiltration into the brain and improved survival in the animal model of cerebral ischemia. Using transgenic knockout models devoid of certain immune cell types and immunodeficient mice supplemented with different immune cell subsets, we dissected the functional contribution of NKG2D signaling by different NKG2D-expressing cells in stroke pathophysiology. The observed effect of NKG2D signaling in stroke progression was shown to be predominantly mediated by natural killer and CD8+ T cells. Transfer of T cells with monovariant T-cell receptors into immunodeficient mice with and without pharmacological blockade of NKG2D revealed activation of CD8+ T cells irrespective of antigen specificity. Detection of the NKG2D receptor and its ligands in brain samples of patients with stroke strengthens the relevance of preclinical observations in human disease. Conclusions Our findings provide a mechanistic insight into NKG2D-dependent natural killer- and T-cell-mediated effects in stroke pathophysiology.
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Affiliation(s)
- Christina David
- Department of Neurology With Center for Translational Neuro- and Behavioral Sciences (C-TNBS) University Hospital Essen, University Duisburg-Essen Essen Germany
| | - Tobias Ruck
- Department of Neurology, Medical Faculty Heinrich-Heine-University Düsseldorf Germany
| | - Leoni Rolfes
- Department of Neurology, Medical Faculty Heinrich-Heine-University Düsseldorf Germany
| | - Stine Mencl
- Department of Neurology With Center for Translational Neuro- and Behavioral Sciences (C-TNBS) University Hospital Essen, University Duisburg-Essen Essen Germany
| | - Peter Kraft
- Department of Neurology Hospital Main-Spessart Lohr am Main Germany
- Department of Neurology University Hospital Würzburg Würzburg Germany
| | | | - Christina B Schroeter
- Department of Neurology, Medical Faculty Heinrich-Heine-University Düsseldorf Germany
| | - Robin Jansen
- Department of Neurology, Medical Faculty Heinrich-Heine-University Düsseldorf Germany
| | - Friederike Langhauser
- Department of Neurology With Center for Translational Neuro- and Behavioral Sciences (C-TNBS) University Hospital Essen, University Duisburg-Essen Essen Germany
| | - Anne K Mausberg
- Department of Neurology With Center for Translational Neuro- and Behavioral Sciences (C-TNBS) University Hospital Essen, University Duisburg-Essen Essen Germany
| | - Anke C Fender
- Department of Pharmacology University Hospital Essen, University of Duisburg-Essen Essen Germany
| | - Sven G Meuth
- Department of Neurology, Medical Faculty Heinrich-Heine-University Düsseldorf Germany
| | - Christoph Kleinschnitz
- Department of Neurology With Center for Translational Neuro- and Behavioral Sciences (C-TNBS) University Hospital Essen, University Duisburg-Essen Essen Germany
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Anang V, Singh A, Kottarath SK, Verma C. Receptors of immune cells mediates recognition for tumors. PROGRESS IN MOLECULAR BIOLOGY AND TRANSLATIONAL SCIENCE 2023; 194:219-267. [PMID: 36631194 DOI: 10.1016/bs.pmbts.2022.09.009] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
Over the last few decades, the immune system has been steered toward eradication of cancer cells with the help of cancer immunotherapy. T cells, B cells, monocytes/macrophages, dendritic cells, T-reg cells, and natural killer (NK) cells are some of the numerous immune cell types that play a significant part in cancer cell detection and reduction of inflammation, and the antitumor response. Briefly stated, chimeric antigen receptors, adoptive transfer and immune checkpoint modulators are currently the subjects of research focus for successful immunotherapy-based treatments for a variety of cancers. This chapter discusses ongoing investigations on the mechanisms and recent developments by which receptors of immune cells especially that of lymphocytes and monocytes/macrophages regulate the detection of immune system leading to malignancies. We will also be looking into the treatment strategies based on these mechanisms.
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Affiliation(s)
- Vandana Anang
- International Center for Genetic Engineering and Biotechnology (ICGEB), New Delhi, India
| | | | - Sarat Kumar Kottarath
- Department of Experimental Therapeutics, MD Anderson Cancer Center, Huston, TX, United States.
| | - Chaitenya Verma
- Department of Pathology, Wexner Medical Center, Ohio State University, Columbus, OH, United States.
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Yaping W, Zhe W, Zhuling C, Ruolei L, Pengyu F, Lili G, Cheng J, Bo Z, Liuyin L, Guangdong H, Yaoling W, Niuniu H, Rui L. The soldiers needed to be awakened: Tumor-infiltrating immune cells. Front Genet 2022; 13:988703. [PMID: 36246629 PMCID: PMC9558824 DOI: 10.3389/fgene.2022.988703] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2022] [Accepted: 08/29/2022] [Indexed: 11/18/2022] Open
Abstract
In the tumor microenvironment, tumor-infiltrating immune cells (TIICs) are a key component. Different types of TIICs play distinct roles. CD8+ T cells and natural killer (NK) cells could secrete soluble factors to hinder tumor cell growth, whereas regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs) release inhibitory factors to promote tumor growth and progression. In the meantime, a growing body of evidence illustrates that the balance between pro- and anti-tumor responses of TIICs is associated with the prognosis in the tumor microenvironment. Therefore, in order to boost anti-tumor response and improve the clinical outcome of tumor patients, a variety of anti-tumor strategies for targeting TIICs based on their respective functions have been developed and obtained good treatment benefits, including mainly immune checkpoint blockade (ICB), adoptive cell therapies (ACT), chimeric antigen receptor (CAR) T cells, and various monoclonal antibodies. In recent years, the tumor-specific features of immune cells are further investigated by various methods, such as using single-cell RNA sequencing (scRNA-seq), and the results indicate that these cells have diverse phenotypes in different types of tumors and emerge inconsistent therapeutic responses. Hence, we concluded the recent advances in tumor-infiltrating immune cells, including functions, prognostic values, and various immunotherapy strategies for each immune cell in different tumors.
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Affiliation(s)
- Wang Yaping
- Department of Thyroid, Breast and Vascular Surgery, Xijing Hospital, Fourth Military Medical University, Xi’an, China
| | - Wang Zhe
- Department of Thyroid, Breast and Vascular Surgery, Xijing Hospital, Fourth Military Medical University, Xi’an, China
| | - Chu Zhuling
- Department of General Surgery, Eastern Theater Air Force Hospital of PLA, Nanjing, China
| | - Li Ruolei
- Department of Thyroid, Breast and Vascular Surgery, Xijing Hospital, Fourth Military Medical University, Xi’an, China
| | - Fan Pengyu
- Department of Thyroid, Breast and Vascular Surgery, Xijing Hospital, Fourth Military Medical University, Xi’an, China
| | - Guo Lili
- Department of Thyroid, Breast and Vascular Surgery, Xijing Hospital, Fourth Military Medical University, Xi’an, China
| | - Ji Cheng
- Department of Thyroid, Breast and Vascular Surgery, Xijing Hospital, Fourth Military Medical University, Xi’an, China
| | - Zhang Bo
- Department of Thyroid, Breast and Vascular Surgery, Xijing Hospital, Fourth Military Medical University, Xi’an, China
| | - Liu Liuyin
- Department of Thyroid, Breast and Vascular Surgery, Xijing Hospital, Fourth Military Medical University, Xi’an, China
| | - Hou Guangdong
- Department of Urology, Xijing Hospital, Fourth Military Medical University, Xi’an, China
| | - Wang Yaoling
- Department of Geriatrics, Union Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Hou Niuniu
- Department of Thyroid, Breast and Vascular Surgery, Xijing Hospital, Fourth Military Medical University, Xi’an, China
- Department of General Surgery, Eastern Theater Air Force Hospital of PLA, Nanjing, China
- *Correspondence: Hou Niuniu, ; Ling Rui,
| | - Ling Rui
- Department of Thyroid, Breast and Vascular Surgery, Xijing Hospital, Fourth Military Medical University, Xi’an, China
- *Correspondence: Hou Niuniu, ; Ling Rui,
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Tomaz D, Pereira PM, Guerra N, Dyson J, Gould K, Henriques R. Nanoscale Colocalization of NK Cell Activating and Inhibitory Receptors Controls Signal Integration. Front Immunol 2022; 13:868496. [PMID: 35720315 PMCID: PMC9198454 DOI: 10.3389/fimmu.2022.868496] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2022] [Accepted: 04/04/2022] [Indexed: 11/13/2022] Open
Abstract
Natural killer (NK) cell responses depend on the balance of signals from inhibitory and activating receptors. However, how the integration of antagonistic signals occurs upon NK cell-target cell interaction is not fully understood. Here we provide evidence that NK cell inhibition via the inhibitory receptor Ly49A is dependent on its relative colocalization at the nanometer scale with the activating receptor NKG2D upon immune synapse (IS) formation. NKG2D and Ly49A signal integration and colocalization were studied using NKG2D-GFP and Ly49A-RFP-expressing primary NK cells, forming ISs with NIH3T3 target cells, with or without the expression of single-chain trimer (SCT) H2-Dd and an extended form of SCT H2-Dd-CD4 MHC-I molecules. Nanoscale colocalization was assessed by Förster resonance energy transfer between NKG2D-GFP and Ly49A-RFP and measured for each synapse. In the presence of their respective cognate ligands, NKG2D and Ly49A colocalize at the nanometer scale, leading to NK cell inhibition. However, increasing the size of the Ly49A ligand reduced the nanoscale colocalization with NKG2D, consequently impairing Ly49A-mediated inhibition. Thus, our data shows that NK cell signal integration is critically dependent on the dimensions of NK cell ligand-receptor pairs by affecting their relative nanometer-scale colocalization at the IS. Our results together suggest that the balance of NK cell signals and NK cell responses is determined by the relative nanoscale colocalization of activating and inhibitory receptors in the immune synapse.
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Affiliation(s)
- David Tomaz
- Department of Immunology, Wright-Fleming Institute, Imperial College London, London, United Kingdom
- Department of Immunology, Hammersmith Hospital, Imperial College London, London, United Kingdom
| | - Pedro Matos Pereira
- Medical Research Council Laboratory for Molecular Cell Biology, University College London, London, United Kingdom
- Bacterial Cell Biology, Instituto de Tecnologia Química e Biológica António Xavier, Universidade Nova de Lisboa, Oeiras, Portugal
| | - Nadia Guerra
- Division of Cell and Molecular Biology, Faculty of Natural Sciences, Imperial College London, London, United Kingdom
| | - Julian Dyson
- Department of Immunology, Hammersmith Hospital, Imperial College London, London, United Kingdom
| | - Keith Gould
- Department of Immunology, Wright-Fleming Institute, Imperial College London, London, United Kingdom
| | - Ricardo Henriques
- Medical Research Council Laboratory for Molecular Cell Biology, University College London, London, United Kingdom
- Division of Infection and Immunity, University College London, London, United Kingdom
- Optical Cell Biology Lab, Instituto Gulbenkian de Ciência, Oeiras, Portugal
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Dong R, Zhang Y, Xiao H, Zeng X. Engineering γδ T Cells: Recognizing and Activating on Their Own Way. Front Immunol 2022; 13:889051. [PMID: 35603176 PMCID: PMC9120431 DOI: 10.3389/fimmu.2022.889051] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2022] [Accepted: 04/11/2022] [Indexed: 11/25/2022] Open
Abstract
Adoptive cell therapy (ACT) with engineered T cells has emerged as a promising strategy for the treatment of malignant tumors. Among them, there is great interest in engineered γδ T cells for ACT. With both adaptive and innate immune characteristics, γδ T cells can be activated by γδ TCRs to recognize antigens in a MHC-independent manner, or by NK receptors to recognize stress-induced molecules. The dual recognition system enables γδ T cells with unique activation and cytotoxicity profiles, which should be considered for the design of engineered γδ T cells. However, the current designs of engineered γδ T cells mostly follow the strategies that used in αβ T cells, but not making good use of the specific characteristics of γδ T cells. Therefore, it is no surprising that current engineered γδ T cells in preclinical or clinical trials have limited efficacy. In this review, we summarized the patterns of antigen recognition of γδ T cells and the features of signaling pathways for the functions of γδ T cells. This review will additionally discuss current progress in engineered γδ T cells and provide insights in the design of engineered γδ T cells based on their specific characteristics.
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Affiliation(s)
- Ruoyu Dong
- Department of Hematology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Yixi Zhang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Haowen Xiao
- Department of Hematology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Xun Zeng
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
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10
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Campos-Silva C, López-Borrego S, Felgueres MJ, Esteso G, Vales-Gomez M. NKG2D Ligands in Liquid Biopsy: The Importance of Soluble and Vesicle-Bound Proteins for Immune Modulation. Crit Rev Immunol 2022; 42:21-40. [PMID: 36374819 DOI: 10.1615/critrevimmunol.2022045263] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2023]
Abstract
The identification of biomarkers allowing diagnostics, prognostics and patient classification is still a challenge in oncological research for patient management. Improvements in patient survival achieved with immunotherapies substantiate that biomarker studies rely not only on cellular pathways contributing to the pathology, but also on the immune competence of the patient. If these immune molecules can be studied in a non-invasive manner, the benefit for patients and clinicians is obvious. The immune receptor Natural Killer Group 2 Member D (NKG2D) represents one of the main systems involved in direct recognition of tumor cells by effector lymphocytes (T and Natural Killer cells), and in immune evasion. The biology of NKG2D and its ligands comprises a complex network of cellular pathways leading to the expression of these tumor-associated ligands on the cell surface or to their release either as soluble proteins, or in extracellular vesicles that potently inhibit NKG2D-mediated responses. Increased levels of NKG2D-ligands in patient serum correlate with tumor progression and poor prognosis; however, most studies did not test the biochemical form of these molecules. Here we review the biology of the NKG2D receptor and ligands, their role in cancer and in patient response to immunotherapies, as well as the changes provoked in this system by non-immune cancer therapies. Further, we discuss the use of NKG2D-L in liquid biopsy, including methods to analyse vesicle-associated proteins. We propose that the evaluation in cancer patients of the whole NKG2D system can provide crucial information about patient immune competence and risk of tumor progression.
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Affiliation(s)
- Carmen Campos-Silva
- Department of Immunology and Oncology, National Centre for Biotechnology, Spanish National Research Council (CNB-CSIC), Madrid, Spain
| | - Silvia López-Borrego
- Department of Immunology and Oncology, National Centre for Biotechnology, Spanish National Research Council (CNB-CSIC), Madrid, Spain
| | - María José Felgueres
- Department of Immunology and Oncology, National Centre for Biotechnology, Spanish National Research Council (CNB-CSIC), Madrid, Spain
| | - Gloria Esteso
- Department of Immunology and Oncology, National Centre for Biotechnology, Spanish National Research Council (CNB-CSIC), Madrid, Spain
| | - Mar Vales-Gomez
- Department of Immunology and Oncology, National Centre for Biotechnology, Spanish National Research Council (CNB-CSIC), Madrid, Spain
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Roma S, Carpen L, Raveane A, Bertolini F. The Dual Role of Innate Lymphoid and Natural Killer Cells in Cancer. from Phenotype to Single-Cell Transcriptomics, Functions and Clinical Uses. Cancers (Basel) 2021; 13:cancers13205042. [PMID: 34680190 PMCID: PMC8533946 DOI: 10.3390/cancers13205042] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2021] [Revised: 10/05/2021] [Accepted: 10/06/2021] [Indexed: 02/07/2023] Open
Abstract
Simple Summary Innate lymphoid cells (ILCs), a family of innate immune cells including natural killers (NKs), play a multitude of roles in first-line cancer control, in escape from immunity and in cancer progression. In this review, we summarize preclinical and clinical data on ILCs and NK cells concerning their phenotype, function and clinical applications in cellular therapy trials. We also describe how single-cell transcriptome sequencing has been used and forecast how it will be used to better understand ILC and NK involvement in cancer control and progression as well as their therapeutic potential. Abstract The role of innate lymphoid cells (ILCs), including natural killer (NK) cells, is pivotal in inflammatory modulation and cancer. Natural killer cell activity and count have been demonstrated to be regulated by the expression of activating and inhibitory receptors together with and as a consequence of different stimuli. The great majority of NK cell populations have an anti-tumor activity due to their cytotoxicity, and for this reason have been used for cellular therapies in cancer patients. On the other hand, the recently classified helper ILCs are fundamentally involved in inflammation and they can be either helpful or harmful in cancer development and progression. Tissue niche seems to play an important role in modulating ILC function and conversion, as observed at the transcriptional level. In the past, these cell populations have been classified by the presence of specific cellular receptor markers; more recently, due to the advent of single-cell RNA sequencing (scRNA-seq), it has been possible to also explore them at the transcriptomic level. In this article we review studies on ILC (and NK cell) classification, function and their involvement in cancer. We also summarize the potential application of NK cells in cancer therapy and give an overview of the most recent studies involving ILCs and NKs at scRNA-seq, focusing on cancer. Finally, we provide a resource for those who wish to start single-cell transcriptomic analysis on the context of these innate lymphoid cell populations.
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12
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Chen J, Moore A, Ringshausen I. ZAP-70 Shapes the Immune Microenvironment in B Cell Malignancies. Front Oncol 2020; 10:595832. [PMID: 33194762 PMCID: PMC7653097 DOI: 10.3389/fonc.2020.595832] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2020] [Accepted: 09/17/2020] [Indexed: 12/12/2022] Open
Abstract
Zeta-chain-associated protein kinase-70 (ZAP-70) is a tyrosine kinase mainly expressed in T cells, NK cells and a subset of B cells. Primarily it functions in T cell receptor (TCR) activation through its tyrosine kinase activity. Aberrant expression of ZAP-70 has been evidenced in different B cell malignancies, with high expression of ZAP-70 in a subset of patients with Chronic Lymphocytic Leukemia (CLL), associating with unfavorable disease outcomes. Previous studies to understand the mechanisms underlying this correlation have been focused on tumor intrinsic mechanisms, including the activation of B cell receptor (BCR) signaling. Recent evidence also suggests that ZAP-70, intrinsically expressed in tumor cells, can modulate the cross-talk between malignant B cells and the immune environment, implying a more complex role of ZAP-70 in the pathogenesis of B cell malignancies. Meanwhile, the indispensible roles of ZAP-70 in T cell and NK cell activation also demonstrate that the autologous expression of ZAP-70 in the immune environment can be a central target in modulation of tumor immunity. Here we review the evidences of the link between ZAP-70 and tumor immunology in the microenvironment in B cell malignancies. Considering an emerging role of immunotherapies in treating these conditions, understanding the distinct molecular functions of ZAP-70 in a broader cellular context could ultimately benefit patient care.
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Affiliation(s)
| | | | - Ingo Ringshausen
- Department of Haematology, Jeffrey Cheah Biomedical Centre, Wellcome Trust/MRC Cambridge Stem Cell Institute, University of Cambridge, Cambridge, United Kingdom
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13
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Meza Guzman LG, Keating N, Nicholson SE. Natural Killer Cells: Tumor Surveillance and Signaling. Cancers (Basel) 2020; 12:cancers12040952. [PMID: 32290478 PMCID: PMC7226588 DOI: 10.3390/cancers12040952] [Citation(s) in RCA: 52] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2020] [Revised: 04/03/2020] [Accepted: 04/09/2020] [Indexed: 12/17/2022] Open
Abstract
Natural killer (NK) cells play a pivotal role in cancer immunotherapy due to their innate ability to detect and kill tumorigenic cells. The decision to kill is determined by the expression of a myriad of activating and inhibitory receptors on the NK cell surface. Cell-to-cell engagement results in either self-tolerance or a cytotoxic response, governed by a fine balance between the signaling cascades downstream of the activating and inhibitory receptors. To evade a cytotoxic immune response, tumor cells can modulate the surface expression of receptor ligands and additionally, alter the conditions in the tumor microenvironment (TME), tilting the scales toward a suppressed cytotoxic NK response. To fully harness the killing power of NK cells for clinical benefit, we need to understand what defines the threshold for activation and what is required to break tolerance. This review will focus on the intracellular signaling pathways activated or suppressed in NK cells and the roles signaling intermediates play during an NK cytotoxic response.
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Affiliation(s)
- Lizeth G. Meza Guzman
- The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia;
- Department of Medical Biology, The University of Melbourne, Parkville, VIC 3010, Australia
- Correspondence: (L.G.M.G.); (S.E.N.); Tel.: +61-9345-2555 (S.E.N.)
| | - Narelle Keating
- The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia;
- Department of Medical Biology, The University of Melbourne, Parkville, VIC 3010, Australia
| | - Sandra E. Nicholson
- The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia;
- Department of Medical Biology, The University of Melbourne, Parkville, VIC 3010, Australia
- Correspondence: (L.G.M.G.); (S.E.N.); Tel.: +61-9345-2555 (S.E.N.)
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14
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Campos-Silva C, Kramer MK, Valés-Gómez M. NKG2D-ligands: Putting everything under the same umbrella can be misleading. HLA 2019. [PMID: 29521021 DOI: 10.1111/tan.13246] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
NKG2D is a key receptor for the activation of immune effector cells, mainly Natural Killer cells and T lymphocytes, in infection, cancer and autoimmune diseases. Since the detection of ligands for NKG2D in sera of cancer patients is, in many human models, indicative of prognosis, a large number of studies have been undertaken to improve understanding of the biology regulating this receptor and its ligands, with the aim of translating this knowledge into clinical practice. Although it is becoming clear that the NKG2D system can be used as a tool for diagnosis and manipulated for therapy, some questions remain open due to the complexity associated with the existence of a large number of ligands, each one of them displaying distinct biological properties. In this review, we have highlighted some key aspects of this system that differ between humans and mice, including the properties of NKG2D, as well as the genetic and biochemical complexity of NKG2D-ligands. All of these features affect the characteristics of the immune response exerted by NKG2D-expressing cells and are likely to be important factors in the clearance of a tumour or the development of autoimmunity. Implementation of more global analyses, including information on genotype, transcription and protein properties (cellular vs released to the blood stream) of NKG2D-ligands expressed in patients will be necessary to fully understand the links between this system and disease progression.
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Affiliation(s)
- C Campos-Silva
- Department of Immunology and Oncology, National Centre for Biotechnology, CNB-CSIC, Madrid, Spain
| | - M K Kramer
- Department of Immunology and Oncology, National Centre for Biotechnology, CNB-CSIC, Madrid, Spain
| | - M Valés-Gómez
- Department of Immunology and Oncology, National Centre for Biotechnology, CNB-CSIC, Madrid, Spain
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15
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Biassoni R, Malnati MS. Human Natural Killer Receptors, Co-Receptors, and Their Ligands. ACTA ACUST UNITED AC 2019; 121:e47. [PMID: 30040219 DOI: 10.1002/cpim.47] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
In the last 20 years, the study of human natural killer (NK) cells has moved from the first molecular characterizations of very few receptor molecules to the identification of a plethora of receptors displaying surprisingly divergent functions. We have contributed to the description of inhibitory receptors and their signaling pathways, important in fine regulation in many cell types, but unknown until their discovery in the NK cells. Inhibitory function is central to regulating NK-mediated cytolysis, with different molecular structures evolving during speciation to assure its persistence. More recently, it has become possible to characterize the NK triggering receptors mediating natural cytotoxicity, unveiling the existence of a network of cellular interactions between effectors of both natural and adaptive immunity. This unit reviews the contemporary history of molecular studies of receptors and ligands involved in NK cell function, characterizing the ligands of the triggering receptor and the mechanisms for finely regulating their expression in pathogen-infected or tumor cells. © 2018 by John Wiley & Sons, Inc.
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Affiliation(s)
- Roberto Biassoni
- IRCCS Istituto Giannina Gaslini, Laboratory of Molecular Medicine, Genova, Italy
| | - Mauro S Malnati
- IRCCS Ospedale San Raffaele, Unit of Human Virology, Division of Immunology, Transplantation and Infectious Diseases, Milan, Italy
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16
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Sheppard S, Ferry A, Guedes J, Guerra N. The Paradoxical Role of NKG2D in Cancer Immunity. Front Immunol 2018; 9:1808. [PMID: 30150983 PMCID: PMC6099450 DOI: 10.3389/fimmu.2018.01808] [Citation(s) in RCA: 48] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2018] [Accepted: 07/23/2018] [Indexed: 12/12/2022] Open
Abstract
The activating receptor NKG2D and its ligands are recognized as a potent immune axis that controls tumor growth and microbial infections. With regards to cancer surveillance, various studies have demonstrated the antitumor function mediated by NKG2D on natural killer cells and on conventional and unconventional T cells. The use of NKG2D-deficient mice established the importance of NKG2D in delaying tumor development in transgenic mouse models of cancer. However, we recently demonstrated an unexpected, flip side to this coin, the ability for NKG2D to contribute to tumor growth in a model of inflammation-driven liver cancer. With a focus on the liver, here, we review current knowledge of NKG2D-mediated tumor surveillance and discuss evidence supporting a dual role for NKG2D in cancer immunity. We postulate that in certain advanced cancers, expression of ligands for NKG2D can drive cancer progression rather than rejection. We propose that the nature of the microenvironment within and surrounding tumors impacts the outcome of NKG2D activation. In a form of autoimmune attack, NKG2D promotes tissue damage, mostly in the inflamed tissue adjacent to the tumor, facilitating tumor progression while being ineffective at rejecting transformed cells in the tumor bed.
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Affiliation(s)
- Sam Sheppard
- Department of Life Sciences, Imperial College London, London, United Kingdom.,Memorial Sloan Kettering Cancer Center, Zuckerman Research Center, New York, NY, United States
| | - Amir Ferry
- Department of Life Sciences, Imperial College London, London, United Kingdom
| | - Joana Guedes
- Department of Life Sciences, Imperial College London, London, United Kingdom
| | - Nadia Guerra
- Department of Life Sciences, Imperial College London, London, United Kingdom
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17
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Abstract
Natural killer (NK) cells express an array of germ-line encoded receptors that are capable of triggering cytotoxicity. NK cells tend to express many members of a given family of signalling molecules. The presence of many activating receptors and many members of a given family of signalling molecules can enable NK cells to detect different kinds of target cells, and to mount different kinds of responses. This contributes also to the robustness of NK cells responses; cytotoxic functions of NK cells often remain unaffected in the absence of selected signalling molecules. NK cells express many MHC-I-specific inhibitory receptors. Signals from MHC-I-specific inhibitory receptors tightly control NK cell cytotoxicity and, paradoxically, maintain NK cells in a state of proper responsiveness. This review provides a brief overview of the events that underlie NK cell activation, and how signals from inhibitory receptors intercept NK cell activation to prevent inappropriate triggering of cytotoxicity.
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Affiliation(s)
- Santosh Kumar
- CSIR-Centre for Cellular and Molecular Biology, Hyderabad, Telangana, India
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18
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Wensveen FM, Jelenčić V, Polić B. NKG2D: A Master Regulator of Immune Cell Responsiveness. Front Immunol 2018; 9:441. [PMID: 29568297 PMCID: PMC5852076 DOI: 10.3389/fimmu.2018.00441] [Citation(s) in RCA: 173] [Impact Index Per Article: 24.7] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2017] [Accepted: 02/19/2018] [Indexed: 01/11/2023] Open
Abstract
NKG2D is an activating receptor that is mostly expressed on cells of the cytotoxic arm of the immune system. Ligands of NKG2D are normally of low abundance, but can be induced in virtually any cell in response to stressors, such as infection and oncogenic transformation. Engagement of NKG2D stimulates the production of cytokines and cytotoxic molecules and traditionally this receptor is, therefore, viewed as a molecule that mediates direct responses against cellular threats. However, accumulating evidence indicates that this classical view is too narrow. During NK cell development, engagement of NKG2D has a long-term impact on the expression of NK cell receptors and their responsiveness to extracellular cues, suggesting a role in NK cell education. Upon chronic NKG2D engagement, both NK and T cells show reduced responsiveness of a number of activating receptors, demonstrating a role of NKG2D in induction of peripheral tolerance. The image that emerges is that NKG2D can mediate both inhibitory and activating signals, which depends on the intensity and duration of ligand engagement. In this review, we provide an overview of the impact of NKG2D stimulation during hematopoietic development and during acute and chronic stimulation in the periphery on responsiveness of other receptors than NKG2D. We propose that NKG2D interprets the context of the immunological environment through detection of cellular cues and in response sets the appropriate activation threshold for a large number of immune receptors. This perspective is of particular importance for future therapies that aim to exploit NKG2D signaling to fight tumors or infection.
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Affiliation(s)
- Felix M Wensveen
- Department of Histology and Embryology, Faculty of Medicine, University of Rijeka, Rijeka, Croatia
| | - Vedrana Jelenčić
- Department of Histology and Embryology, Faculty of Medicine, University of Rijeka, Rijeka, Croatia
| | - Bojan Polić
- Department of Histology and Embryology, Faculty of Medicine, University of Rijeka, Rijeka, Croatia
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19
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Nabekura T, Gotthardt D, Niizuma K, Trsan T, Jenus T, Jonjic S, Lanier LL. Cutting Edge: NKG2D Signaling Enhances NK Cell Responses but Alone Is Insufficient To Drive Expansion during Mouse Cytomegalovirus Infection. THE JOURNAL OF IMMUNOLOGY 2017; 199:1567-1571. [PMID: 28760883 DOI: 10.4049/jimmunol.1700799] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/02/2017] [Accepted: 07/12/2017] [Indexed: 12/25/2022]
Abstract
NK cells play a critical role in host defense against viruses. In this study, we investigated the role of NKG2D in the expansion of NK cells after mouse CMV (MCMV) infection. Wild-type and NKG2D-deficient (Klrk1-/- ) Ly49H+ NK cells proliferated robustly when infected with MCMV strains engineered to allow expression of NKG2D ligands, which enhanced the response of wild-type NK cells. Naive NK cells exclusively express NKG2D-L, which pairs only with DAP10, whereas NKG2D-S expressed by activated NK cells pairs with DAP10 and DAP12, similar to Ly49H. However, NKG2D alone was unable to drive robust expansion of Ly49H- NK cells when mice were infected with these MCMV strains, likely because NKG2D-S was only transiently expressed postinfection. These findings demonstrate that NKG2D augments Ly49H-dependent proliferation of NK cells; however, NKG2D signaling alone is inadequate for expansion of NK cells, likely due to only transient expression of the NKG2D-DAP12 complex.
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Affiliation(s)
- Tsukasa Nabekura
- Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA 94143.,Parker Institute for Cancer Immunotherapy, San Francisco, CA 94143.,Life Science Center, Tsukuba Advanced Research Alliance, University of Tsukuba, Ibaraki 305-8577, Japan
| | - Dagmar Gotthardt
- Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA 94143.,Parker Institute for Cancer Immunotherapy, San Francisco, CA 94143
| | - Kouta Niizuma
- Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA 94143.,Ph.D. Program in Human Biology, School of Integrative and Global Majors, University of Tsukuba, Ibaraki 305-8575, Japan; and
| | - Tihana Trsan
- Department of Histology and Embryology, Faculty of Medicine, University of Rijeka, Rijeka 51000, Croatia
| | - Tina Jenus
- Department of Histology and Embryology, Faculty of Medicine, University of Rijeka, Rijeka 51000, Croatia
| | - Stipan Jonjic
- Department of Histology and Embryology, Faculty of Medicine, University of Rijeka, Rijeka 51000, Croatia
| | - Lewis L Lanier
- Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA 94143; .,Parker Institute for Cancer Immunotherapy, San Francisco, CA 94143
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20
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The Effects of Artemisinin on the Cytolytic Activity of Natural Killer (NK) Cells. Int J Mol Sci 2017; 18:ijms18071600. [PMID: 28737711 PMCID: PMC5536087 DOI: 10.3390/ijms18071600] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2017] [Revised: 07/13/2017] [Accepted: 07/21/2017] [Indexed: 01/14/2023] Open
Abstract
Artemisinin, a chemical compound used for the treatment of malaria, has been known to show anti-cancer activity. However, the effect of this chemical on natural killer (NK) cells, which are involved in tumor killing, remains unknown. Here, we demonstrate that artemisinin exerts a potent anti-cancer effect by activating NK cells. NK-92MI cells pre-treated with artemisinin were subjected to a cytotoxicity assay using K562 cells. The results showed that artemisinin significantly enhances the cytolytic activity of NK cells in a dose-dependent manner. Additionally, the artemisinin-enhanced cytotoxic effect of NK-92MI cells on tumor cells was accompanied by the stimulation of granule exocytosis, as evidenced by the detection of CD107a expression in NK cells. Moreover, this enhancement of cytotoxicity by artemisinin was also observed in human primary NK cells from peripheral blood. Our results suggest that artemisinin enhances human NK cell cytotoxicity and degranulation. This is the first evidence that artemisinin exerts antitumor activity by enhancing NK cytotoxicity. Therefore, these results provide a deeper understanding of the action of artemisinin and will contribute to the development and application of this class of compounds in cancer treatment strategies.
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21
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Fasbender F, Claus M, Wingert S, Sandusky M, Watzl C. Differential Requirements for Src-Family Kinases in SYK or ZAP70-Mediated SLP-76 Phosphorylation in Lymphocytes. Front Immunol 2017; 8:789. [PMID: 28736554 PMCID: PMC5500614 DOI: 10.3389/fimmu.2017.00789] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2017] [Accepted: 06/22/2017] [Indexed: 01/10/2023] Open
Abstract
In a synthetic biology approach using Schneider (S2) cells, we show that SLP-76 is directly phosphorylated at tyrosines Y113 and Y128 by SYK in the presence of ITAM-containing adapters such as CD3ζ, DAP12, or FcεRγ. This phosphorylation was dependent on at least one functional ITAM and a functional SH2 domain within SYK. Inhibition of Src-kinases by inhibitors PP1 and PP2 did not reduce SLP-76 phosphorylation in S2 cells, suggesting an ITAM and SYK dependent, but Src-kinase independent signaling pathway. This direct ITAM/SYK/SLP-76 signaling pathway therefore differs from previously described ITAM signaling. However, the SYK-family kinase ZAP70 required the additional co-expression of the Src-family kinases Fyn or Lck to efficiently phosphorylate SLP-76 in S2 cells. This difference in Src-family kinase dependency of SYK versus ZAP70-mediated ITAM-based signaling was further demonstrated in human lymphocytes. ITAM signaling in ZAP70-expressing T cells was dependent on the activity of Src-family kinases. In contrast, Src-family kinases were partially dispensable for ITAM signaling in SYK-expressing B cells or in natural killer cells, which express SYK and ZAP70. This demonstrates that SYK can signal using a Src-kinase independent ITAM-based signaling pathway, which may be involved in calibrating the threshold for lymphocyte activation.
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Affiliation(s)
- Frank Fasbender
- Leibniz Research Centre for Working Environment and Human Factors, IfADo, TU-Dortmund, Dortmund, Germany
| | - Maren Claus
- Leibniz Research Centre for Working Environment and Human Factors, IfADo, TU-Dortmund, Dortmund, Germany
| | - Sabine Wingert
- Leibniz Research Centre for Working Environment and Human Factors, IfADo, TU-Dortmund, Dortmund, Germany
| | - Mina Sandusky
- Leibniz Research Centre for Working Environment and Human Factors, IfADo, TU-Dortmund, Dortmund, Germany
| | - Carsten Watzl
- Leibniz Research Centre for Working Environment and Human Factors, IfADo, TU-Dortmund, Dortmund, Germany
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22
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Jelenčić V, Lenartić M, Wensveen FM, Polić B. NKG2D: A versatile player in the immune system. Immunol Lett 2017; 189:48-53. [PMID: 28414183 DOI: 10.1016/j.imlet.2017.04.006] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2017] [Accepted: 04/11/2017] [Indexed: 12/21/2022]
Abstract
NKG2D is known as a potent activating receptor of the immune system. It is expressed on a multitude of immune cells, including NK cells and different subsets of T cells. NKG2D recognizes various MHC I-like ligands that are induced on target cells exposed to stressors such as viral infection, DNA damage and oncological transformation. NKG2D drives or facilitates cytotoxic and cytokine responses towards cells expressing its ligands to eliminate the threat. Therefore, NKG2D is usually classified as a sensor that translates cellular stress into activation signals for immune cells. However, more recently it has become evident that NKG2D plays a role beyond direct killing of target cells. Lack of NKG2D affects development of NK cells in the bone marrow, resulting in hyperreactive NK cells. NKG2D deficiency on CD8 T cells affects the ability of effector cells to produce cytokines in response to T cell receptor engagement and reduces their capacity to establish immunological memory. Although NKG2D is not expressed on B cells subsets, lack of this receptor in hematopoietic precursors affects B cell development. Homing of mature B2 cells is altered in NKG2D-deficient mice and they have a strong reduction in peripheral B1a cell numbers, resulting in increased susceptibility to bacterial infections. The exact molecular mechanisms via which NKG2D mediates these versatile functions is still being explored, but appears to depend on the control of activation thresholds, either in hematopoietic precursors or mature immune cell subsets. In this review, we will elaborate on the underappreciated developmental and regulatory roles of NKG2D.
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Affiliation(s)
- Vedrana Jelenčić
- Department of Histology and Embryology, Faculty of Medicine, University of Rijeka, Rijeka, Croatia
| | - Maja Lenartić
- Department of Histology and Embryology, Faculty of Medicine, University of Rijeka, Rijeka, Croatia
| | - Felix M Wensveen
- Department of Histology and Embryology, Faculty of Medicine, University of Rijeka, Rijeka, Croatia; Department of Experimental Immunology, Amsterdam Medical Center, Amsterdam, The Netherlands
| | - Bojan Polić
- Department of Histology and Embryology, Faculty of Medicine, University of Rijeka, Rijeka, Croatia.
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The Development and Diversity of ILCs, NK Cells and Their Relevance in Health and Diseases. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2017; 1024:225-244. [PMID: 28921473 DOI: 10.1007/978-981-10-5987-2_11] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Next to T and B cells, natural killer (NK) cells are the third largest lymphocyte population. They are recently re-categorized as innate lymphocytes (ILCs), which also include ILC1, ILC2, ILC3, and the lymphoid tissue inducer (LTi) cells. Both NK cells and ILC1 cells are designated as group 1 ILCs because they secrete interferon-γ (IFN-γ) and tumor necrosis factor (TNF). However, in contrast to ILC1 and all other ILCs, NK cells possess potent cytolytic functions that resemble cytotoxic T lymphocytes (CTL). In addition, NK cells express, in a stochastic manner, an array of germ line-encoded activating and inhibitory receptors that recognize the polymorphic regions of major histocompatibility class I (MHC-I) molecules and self-proteins. Recognition of self renders NK cell tolerance to self-healthy tissues, but fail to recognize self ('missing-self') leads to activation to neoplastic transformation and infections of certain viruses. In this chapter, we will summarize the development of NK cells in the context of ILCs, describe the diversity of phenotype and function in blood and tissues, and discuss their involvement in health and diseases in humans.
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24
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Martinez-Chamorro A, Moreno A, Gómez-García M, Cabello MJ, Martin J, Lopez-Nevot MÁ. MICA*A4 protects against ulcerative colitis, whereas MICA*A5.1 is associated with abscess formation and age of onset. Clin Exp Immunol 2016; 184:323-31. [PMID: 26940143 DOI: 10.1111/cei.12786] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/01/2016] [Indexed: 12/15/2022] Open
Abstract
Ulcerative colitis (UC) is one of the two major forms of inflammatory bowel disease, the aetiology of which remains unknown. Several studies have demonstrated the genetic basis of disease, identifying more than 130 susceptibility loci. The major histocompatibility complex class I chain-related gene A (MICA) is a useful candidate to be involved in UC pathogenesis, because it could be important in recognizing the integrity of the epithelial cell and its response to stress. The aim of this study was to analyse the relationship between polymorphisms in the transmembrane domain of MICA and susceptibility to develop UC. A total of 340 patients with UC and 636 healthy controls were genotyped for MICA transmembrane polymorphism using a polymerase chain reaction (PCR) combined with fluorescent technology. Different MICA alleles were determined depending on the PCR product size. The allele MICA*A4 was less frequent in patients than in controls (P = 0·003; OR = 0·643), and this protective role is higher when it forms haplotype with B*27 (P = 0·002; OR = 0·294). The haplotype HLA-B*52/MICA*A6 was also associated with UC [P = 0·001; odds ratio (OR) = 2·914]. No other alleles, genotypes or haplotypes were related with UC risk. Moreover, MICA*A5.1 is associated independently with abscesses (P = 0·002; OR = 3·096) and its frequency is lower in patients diagnosed between ages 17 and 40 years (P = 0·007; OR = 0·633), meaning an extreme age on onset. No association with location, extra-intestinal manifestations or need for surgery was found.
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Affiliation(s)
| | - A Moreno
- Section of Immunology, Hospital Virgen de las Nieves
| | | | - M J Cabello
- Digestive Section, Hospital Virgen de las Nieves
| | - J Martin
- Institute of Parasitology and Biomedicine López-Neyra, CSIC, Granada, Spain
| | - M Á Lopez-Nevot
- Section of Immunology, Hospital Virgen de las Nieves.,University of Granada
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25
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Kirkham CL, Carlyle JR. Complexity and Diversity of the NKR-P1:Clr (Klrb1:Clec2) Recognition Systems. Front Immunol 2014; 5:214. [PMID: 24917862 PMCID: PMC4041007 DOI: 10.3389/fimmu.2014.00214] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2014] [Accepted: 04/28/2014] [Indexed: 11/26/2022] Open
Abstract
The NKR-P1 receptors were identified as prototypical natural killer (NK) cell surface antigens and later shown to be conserved from rodents to humans on NK cells and subsets of T cells. C-type lectin-like in nature, they were originally shown to be capable of activating NK cell function and to recognize ligands on tumor cells. However, certain family members have subsequently been shown to be capable of inhibiting NK cell activity, and to recognize proteins encoded by a family of genetically linked C-type lectin-related ligands. Some of these ligands are expressed by normal, healthy cells, and modulated during transformation, infection, and cellular stress, while other ligands are upregulated during the immune response and during pathological circumstances. Here, we discuss historical and recent developments in NKR-P1 biology that demonstrate this NK receptor–ligand system to be far more complex and diverse than originally anticipated.
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Affiliation(s)
- Christina L Kirkham
- Department of Immunology, University of Toronto, Sunnybrook Research Institute , Toronto, ON , Canada
| | - James R Carlyle
- Department of Immunology, University of Toronto, Sunnybrook Research Institute , Toronto, ON , Canada
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Marcus A, Gowen BG, Thompson TW, Iannello A, Ardolino M, Deng W, Wang L, Shifrin N, Raulet DH. Recognition of tumors by the innate immune system and natural killer cells. Adv Immunol 2014; 122:91-128. [PMID: 24507156 PMCID: PMC4228931 DOI: 10.1016/b978-0-12-800267-4.00003-1] [Citation(s) in RCA: 263] [Impact Index Per Article: 23.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
In recent years, roles of the immune system in immune surveillance of cancer have been explored using a variety of approaches. The roles of the adaptive immune system have been a major emphasis, but increasing evidence supports a role for innate immune effector cells such as natural killer (NK) cells in tumor surveillance. Here, we discuss some of the evidence for roles in tumor surveillance of innate immune cells. In particular, we focus on NK cells and other immune cells that express germline-encoded receptors, often labeled NK receptors. The impact of these receptors and the cells that express them on tumor suppression is summarized. We discuss in detail some of the pathways and events in tumor cells that induce or upregulate cell-surface expression of the ligands for these receptors, and the logic of how those pathways serve to identify malignant, or potentially malignant cells. How tumors often evade tumor suppression mediated by innate killer cells is another major subject of the review. We end with a discussion on some of the implications of the various findings with respect to possible therapeutic approaches.
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Affiliation(s)
- Assaf Marcus
- Department of Molecular and Cell Biology and Cancer Research Laboratory, University of California, Berkeley, USA
| | - Benjamin G Gowen
- Department of Molecular and Cell Biology and Cancer Research Laboratory, University of California, Berkeley, USA
| | - Thornton W Thompson
- Department of Molecular and Cell Biology and Cancer Research Laboratory, University of California, Berkeley, USA
| | - Alexandre Iannello
- Department of Molecular and Cell Biology and Cancer Research Laboratory, University of California, Berkeley, USA
| | - Michele Ardolino
- Department of Molecular and Cell Biology and Cancer Research Laboratory, University of California, Berkeley, USA
| | - Weiwen Deng
- Department of Molecular and Cell Biology and Cancer Research Laboratory, University of California, Berkeley, USA
| | - Lin Wang
- Department of Molecular and Cell Biology and Cancer Research Laboratory, University of California, Berkeley, USA
| | - Nataliya Shifrin
- Department of Molecular and Cell Biology and Cancer Research Laboratory, University of California, Berkeley, USA
| | - David H Raulet
- Department of Molecular and Cell Biology and Cancer Research Laboratory, University of California, Berkeley, USA.
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Ullrich E, Koch J, Cerwenka A, Steinle A. New prospects on the NKG2D/NKG2DL system for oncology. Oncoimmunology 2013; 2:e26097. [PMID: 24353908 PMCID: PMC3862635 DOI: 10.4161/onci.26097] [Citation(s) in RCA: 97] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2013] [Revised: 08/06/2013] [Accepted: 08/09/2013] [Indexed: 11/19/2022] Open
Abstract
The activating immunoreceptor NKG2D endows cytotoxic lymphocytes with the capacity to recognize and eliminate infected or malignant cells. The recognition of such harmful cells is enabled by binding of NKG2D to various MHC class I-related glycoproteins, which are upregulated in the course of viral infection or malignant transformation. The past years have witnessed substantial progress in our understanding of the mechanisms underlying the regulation of NKG2D ligands (NKG2DLs) by malignant cells, of tumor-associated countermeasures promoting escape from NKG2D-dependent immunosurveillance, and of therapeutic measures that may bolster the NKG2D/NKG2DL system against malignancies. Here, we summarize the current knowledge on the NKG2D/NKG2DL system and outline opportunities to exploit the tumoricidal function of NKG2D for anticancer immunotherapy.
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Affiliation(s)
- Evelyn Ullrich
- Children's Hospital; Department of Pediatric Hematology and Oncology; Goethe-University Frankfurt am Main; Frankfurt am Main, Germany ; Center for Cell and Gene Therapy; Goethe University Frankfurt am Main; Frankfurt am Main, Germany
| | - Joachim Koch
- Center for Cell and Gene Therapy; Goethe University Frankfurt am Main; Frankfurt am Main, Germany ; Institute for Biomedical Research: Georg-Speyer-Haus; NK Cell Biology; Frankfurt am Main, Germany
| | - Adelheid Cerwenka
- German Cancer Research Center (DKFZ); Innate Immunity Group; Heidelberg, Germany
| | - Alexander Steinle
- Institute for Molecular Medicine; Goethe-University Frankfurt am Main; Frankfurt am Main, Germany
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Wunderlich P, Glebov K, Kemmerling N, Tien NT, Neumann H, Walter J. Sequential proteolytic processing of the triggering receptor expressed on myeloid cells-2 (TREM2) protein by ectodomain shedding and γ-secretase-dependent intramembranous cleavage. J Biol Chem 2013; 288:33027-36. [PMID: 24078628 DOI: 10.1074/jbc.m113.517540] [Citation(s) in RCA: 224] [Impact Index Per Article: 18.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Triggering receptor expressed on myeloid cells-2 (TREM2) and its signaling adaptor protein TYROBP/DAP12 play important roles in signal transduction in dendritic cells, osteoclasts, tissue macrophages, and microglia. Recently, TREM2 variants have been shown to be linked to late onset Alzheimer disease. Here, we demonstrate that TREM2 undergoes sequential proteolytic processing by ectodomain shedding and intramembrane proteolysis. The C-terminal fragment (CTF) of TREM2 generated by ectodomain shedding is cleaved by γ-secretase. Importantly, pharmacologic and genetic γ-secretase inhibition resulted in accumulation of TREM2 CTF at the plasma membrane that also interacts with the signaling adaptor protein DAP12. Thus, the accumulated TREM2 CTF thereby might limit the interaction of DAP12 with the functional full-length receptor, resulting in decreased DAP12 phosphorylation and impaired metabolism of phosphatidylinositol 4,5-bisphosphate. Together, these data demonstrate γ-secretase-mediated intramembranous proteolysis of TREM2 and functionally link two Alzheimer disease-associated proteins in one signaling pathway.
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Affiliation(s)
- Patrick Wunderlich
- From the Department of Neurology, University of Bonn, 53127 Bonn, Germany and
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Signaling by Fyn-ADAP via the Carma1-Bcl-10-MAP3K7 signalosome exclusively regulates inflammatory cytokine production in NK cells. Nat Immunol 2013; 14:1127-36. [PMID: 24036998 PMCID: PMC3855032 DOI: 10.1038/ni.2708] [Citation(s) in RCA: 69] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2013] [Accepted: 08/09/2013] [Indexed: 11/29/2022]
Abstract
Inflammation is a critical component of the immune response. However, acute or chronic inflammation can be highly destructive. Uncontrolled inflammation forms the basis for allergy, asthma, and multiple autoimmune disorders. Here, we identify a signaling pathway that is exclusively responsible for inflammatory cytokine production but not for cytotoxicity. Recognition of H60+ or CD137L+ tumor cells by murine NK cells led to efficient cytotoxicity and inflammatory cytokine production. Both of these effector functions required Lck, Fyn, PI(3)K-p85α, PI(3)K-p110δ, and PLC-γ2. However, the complex of Fyn and the adapter ADAP exclusively regulated inflammatory cytokine production but not cytotoxicity in NK cells. This unique function of ADAP required a Carma1-Bcl10-MAP3K7 signaling axis. Our results identify molecules that can be targeted to regulate inflammation without compromising NK cell cytotoxicity.
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Hosomi S, Chen Z, Baker K, Chen L, Huang YH, Olszak T, Zeissig S, Wang JH, Mandelboim O, Beauchemin N, Lanier LL, Blumberg RS. CEACAM1 on activated NK cells inhibits NKG2D-mediated cytolytic function and signaling. Eur J Immunol 2013; 43:2473-83. [PMID: 23696226 PMCID: PMC3775953 DOI: 10.1002/eji.201242676] [Citation(s) in RCA: 43] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2012] [Revised: 04/09/2013] [Accepted: 05/17/2013] [Indexed: 12/29/2022]
Abstract
Carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) is expressed on activated natural killer (NK) cells wherein it inhibits lysis of CEACAM1-bearing tumor cell lines. The mechanism for this is unknown. Here, we show that interleukin-2-induced expression of CEACAM1 on both mouse and primary human NK cells impairs the ability of NK gene complex group 2 member D (NKG2D) to stimulate cytolysis of CEACAM1-bearing cells. This process requires the expression of CEACAM1 on the NK cells and on the tumor cells, which is consistent with the involvement of trans-homophilic interactions between CEACAM1. Mechanistically, co-engagement of NKG2D and CEACAM1 results in a biochemical association between these two surface receptors and the recruitment of Src homology phosphatase 1 by CEACAM1 that leads to dephosphorylation of the guanine nucleotide exchange factor Vav1 and blockade of downstream signaling that is associated with the initiation of cytolysis. Thus, CEACAM1 on activated NK cells functions as an inhibitory receptor for NKG2D-mediated cytolysis, which has important implications for understanding the means by which CEACAM1 expression adversely affects tumor immunity.
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Affiliation(s)
- Shuhei Hosomi
- Gastroenterology Division, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA
| | - Zhangguo Chen
- Gastroenterology Division, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA
- Department of Immunology, National Jewish Health, University of Colorado Denver, Denver, CO, USA
| | - Kristi Baker
- Gastroenterology Division, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA
| | - Lanfen Chen
- Gastroenterology Division, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA
| | - Yu-Hwa Huang
- Gastroenterology Division, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA
| | - Torsten Olszak
- Gastroenterology Division, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA
| | - Sebastian Zeissig
- Gastroenterology Division, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA
| | - Jing H. Wang
- Department of Immunology, National Jewish Health, University of Colorado Denver, Denver, CO, USA
| | - Ofer Mandelboim
- Lautenberg Center for General and Tumor Immunology, Hebrew University Hadassah Medical School, Jerusalem, Israel
| | - Nicole Beauchemin
- Goodman Cancer Research Centre and Depts. of Biochemistry, Medicine and Oncology, McGill University, Montreal, Canada
| | - Lewis L. Lanier
- Department of Microbiology and Immunology and the Cancer Research Institute, University of California San Francisco, San Francisco, CA, USA
| | - Richard S. Blumberg
- Gastroenterology Division, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA
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NKG2D triggers cytotoxicity in murine epidermal γδ T cells via PI3K-dependent, Syk/ZAP70-independent signaling pathway. J Invest Dermatol 2013; 134:396-404. [PMID: 23962808 DOI: 10.1038/jid.2013.353] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2013] [Revised: 07/17/2013] [Accepted: 07/29/2013] [Indexed: 01/29/2023]
Abstract
Murine epidermal γδ T cells, known as dendritic epidermal T cells (DETCs), survey tissue stress through the invariant T-cell receptor (TCR) and non-clonotypic receptors such as NKG2D. NKG2D signaling via the DAP10-phosphatidylinositol 3-kinase (PI3K) pathway directly stimulates cytotoxicity in natural killer (NK) cells and costimulates CD8(+) T cells to augment TCR signals. In activated murine NK cells, NKG2D signals also via the DAP12-Syk/ZAP70 pathway that triggers both cytotoxicity and cytokine production. It remains controversial whether NKG2D on DETCs is a primary activating receptor or functions only as a costimulatory receptor, and signaling pathways initiated by NKG2D ligation in DETCs have not been analyzed. We show that stimulation of short-term DETC lines with recombinant NKG2D ligands triggers degranulation (exocytosis of cytotoxic granules) via the PI3K-dependent signaling pathway, but does not induce cytokine production or Syk/ZAP70 activation. Coengagement of TCR or Syk/ZAP70 signaling was not crucial for DETC-mediated killing of NKG2D ligand-expressing target cells. Thus, NKG2D can function as a coactivating stress receptor that directly triggers cytotoxicity in DETCs, at least after priming, via the PI3K-dependent, Syk/ZAP70-independent signaling pathway.
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Brenu EW, Hardcastle SL, Atkinson GM, van Driel ML, Kreijkamp-Kaspers S, Ashton KJ, Staines DR, Marshall-Gradisnik SM. Natural killer cells in patients with severe chronic fatigue syndrome. AUTOIMMUNITY HIGHLIGHTS 2013; 4:69-80. [PMID: 26000145 PMCID: PMC4389023 DOI: 10.1007/s13317-013-0051-x] [Citation(s) in RCA: 44] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/28/2012] [Accepted: 03/06/2013] [Indexed: 02/06/2023]
Abstract
Maintenance of health and physiological homeostasis is a synergistic process involving tight regulation of proteins, transcription factors and other molecular processes. The immune system consists of innate and adaptive immune cells that are required to sustain immunity. The presence of pathogens and tumour cells activates innate immune cells, in particular Natural Killer (NK) cells. Stochastic expression of NK receptors activates either inhibitory or activating signals and results in cytokine production and activation of pathways that result in apoptosis of target cells. Thus, NK cells are a necessary component of the immunological process and aberrations in their functional processes, including equivocal levels of NK cells and cytotoxic activity pre-empts recurrent viral infections, autoimmune diseases and altered inflammatory responses. NK cells are implicated in a number of diseases including chronic fatigue syndrome (CFS). The purpose of this review is to highlight the different profiles of NK cells reported in CFS patients and to determine the extent of NK immune dysfunction in subtypes of CFS patients based on severity in symptoms.
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Affiliation(s)
- E. W. Brenu
- Griffith Health Institute, School of Medical Science, Griffith University, Gold Coast, QLD Australia
- The National Centre for Neuroimmunology and Emerging Diseases, Griffith University, Gold Coast, QLD Australia
- Immunology Research Group, Centre for Medicine and Oral Health, Griffith University, GH1, Room 7.59, Southport, QLD 4215 Australia
| | - S. L. Hardcastle
- Griffith Health Institute, School of Medical Science, Griffith University, Gold Coast, QLD Australia
- The National Centre for Neuroimmunology and Emerging Diseases, Griffith University, Gold Coast, QLD Australia
| | - G. M. Atkinson
- Griffith Health Institute, School of Medical Science, Griffith University, Gold Coast, QLD Australia
- The National Centre for Neuroimmunology and Emerging Diseases, Griffith University, Gold Coast, QLD Australia
| | - M. L. van Driel
- Queensland Health, Gold Coast Public Health Unit, Robina, Gold Coast, QLD Australia
| | | | - K. J. Ashton
- Faculty of Health Sciences and Medicine, Bond University, Robina, QLD Australia
| | - D. R. Staines
- The National Centre for Neuroimmunology and Emerging Diseases, Griffith University, Gold Coast, QLD Australia
- Queensland Health, Gold Coast Public Health Unit, Robina, Gold Coast, QLD Australia
| | - S. M. Marshall-Gradisnik
- Griffith Health Institute, School of Medical Science, Griffith University, Gold Coast, QLD Australia
- The National Centre for Neuroimmunology and Emerging Diseases, Griffith University, Gold Coast, QLD Australia
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Different combinations of cytokines and activating receptor stimuli are required for human natural killer cell functional diversity. Cytokine 2013; 62:58-63. [DOI: 10.1016/j.cyto.2013.02.018] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2012] [Revised: 01/14/2013] [Accepted: 02/11/2013] [Indexed: 11/23/2022]
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Kwon HJ, Kim HS. Signaling for synergistic activation of natural killer cells. Immune Netw 2012; 12:240-6. [PMID: 23396805 PMCID: PMC3566418 DOI: 10.4110/in.2012.12.6.240] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2012] [Revised: 11/12/2012] [Accepted: 11/15/2012] [Indexed: 12/30/2022] Open
Abstract
Natural killer (NK) cells play a pivotal role in early surveillance against virus infection and cellular transformation, and are also implicated in the control of inflammatory response through their effector functions of direct lysis of target cells and cytokine secretion. NK cell activation toward target cell is determined by the net balance of signals transmitted from diverse activating and inhibitory receptors. A distinct feature of NK cell activation is that stimulation of resting NK cells with single activating receptor on its own cannot mount natural cytotoxicity. Instead, specific pairs of co-activation receptors are required to unleash NK cell activation via synergy-dependent mechanism. Because each co-activation receptor uses distinct signaling modules, NK cell synergy relies on the integration of such disparate signals. This explains why the study of the mechanism underlying NK cell synergy is important and necessary. Recent studies revealed that NK cell synergy depends on the integration of complementary signals converged at a critical checkpoint element but not on simple amplification of the individual signaling to overcome intrinsic activation threshold. This review focuses on the signaling events during NK cells activation and recent advances in the study of NK cell synergy.
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Affiliation(s)
- Hyung-Joon Kwon
- Department of Medicine, Graduate School, University of Ulsan College of Medicine, Seoul 138-736, Korea
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Hoover RG, Gullickson G, Kornbluth J. Natural killer lytic-associated molecule plays a role in controlling tumor dissemination and metastasis. Front Immunol 2012; 3:393. [PMID: 23269922 PMCID: PMC3529306 DOI: 10.3389/fimmu.2012.00393] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2012] [Accepted: 12/06/2012] [Indexed: 01/23/2023] Open
Abstract
Natural killer lytic-associated molecule (NKLAM) is an E3 ubiquitin ligase that plays a major role in the cytolytic activity of NK cells. NKLAM is rapidly synthesized and then targeted to the granule membranes of NK cells upon NK activation. Previous studies have shown an essential role for NKLAM in NK killing activity in vitro. These findings were extended to an in vivo model of NK-mediated tumor killing in which NKLAM-deficient knockout (KO) mice injected with B16 melanoma cells were found to have significantly higher numbers of pulmonary tumor nodules than wild-type (WT) mice. To further investigate the role of NKLAM and NK function in tumor immunity in vivo, we utilized additional tumor models to compare tumor development and progression in NKLAM KO and WT mice. Primary tumor growth, dissemination, and metastasis of RMA-S lymphoma cells and E0771 breast cancer cells were evaluated. Both tumor cell lines were stably transfected with constructs that allow expression of green fluorescent protein (GFP), which serves as a tumor-specific marker. Intravenous injection of NK-sensitive RMA-S lymphoma cells resulted in greater dissemination of lymphoma cells in NKLAM KO mice than in WT mice. Lymphoma cells were found in the lymph nodes and bone marrow (BM) of NKLAM KO mice 2 weeks after injection; few detectable tumor cells remained in WT mice. E0771 syngeneic breast cancer cells were injected into the mammary pads of NKLAM KO and WT mice. Primary tumor growth was greater in NKLAM KO than in WT mice. More significantly, there were 4–5-fold more tumor cells in the blood and lungs of NKLAM KO than in WT mice 2 weeks after injection of tumor cells into the mammary pad. These results indicate that NKLAM plays a role in tumor development in vivo, especially in controlling tumor dissemination and metastasis to distant sites.
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Affiliation(s)
- Richard G Hoover
- Department of Pathology, Saint Louis University School of Medicine St. Louis, MO, USA
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Merino E, Abeyweera TP, Firth MA, Zawislak CL, Basu R, Liu X, Sun JC, Huse M. Protein Kinase C-θ Clustering at Immunological Synapses Amplifies Effector Responses in NK Cells. THE JOURNAL OF IMMUNOLOGY 2012; 189:4859-69. [DOI: 10.4049/jimmunol.1200825] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
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Nogusa S, Murasko DM, Gardner EM. Differential effects of stimulatory factors on natural killer cell activities of young and aged mice. J Gerontol A Biol Sci Med Sci 2012; 67:947-54. [PMID: 22454373 PMCID: PMC3436087 DOI: 10.1093/gerona/gls079] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2011] [Accepted: 02/13/2012] [Indexed: 01/10/2023] Open
Abstract
Age-associated influences on natural killer (NK) cell functions following cytokine stimulation were examined in splenocytes from C57BL/6 mice. NK cells of both young and aged mice exhibited significantly increased: interferon-γ production after interleukin (IL)-12 or IL-15 alone or any combination of IL-12, IL-18, and IL-2; cytotoxicity after IL-2 or IL-15; and granzyme B expression after IL-15. The only significant age-associated differences were observed in interferon-γ production after IL-15 or IL-12 + 18 + 2 and in granzyme B expression following IL-2 or IL-15. Perforin expression did not increase following stimulation; however, NK cells from aged mice expressed significantly higher levels than young mice. These results underscore the complexity of the cytokine-induced functional activities of NK cells and illustrate the differential response of NK cells from young and aged mice to cytokine stimulation.
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Affiliation(s)
- Shoko Nogusa
- Department of Biology, Drexel University, Philadelphia, Pennsylvania
| | - Donna M. Murasko
- Department of Biology, Drexel University, Philadelphia, Pennsylvania
| | - Elizabeth M. Gardner
- Department of Food Science and Human Nutrition, Michigan State University,
East Lansing
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Abstract
INTRODUCTION NKG2D (natural killer group 2, member D) is expressed on the surface of all mouse and human NK cells, and subpopulation of T cells. Stimulation of NK cells through NKG2D triggers cell-mediated cytotoxicity and induces the production of cytokines. NKG2D binds to family of unique ligands with structurally similar to MHC class I, however, NKG2D ligands can be up-regulated in their expression on stressed cells including tumor cells unlike conventional MHC class I molecules. Mounting evidences clearly implicate that NKG2D recognition plays an important role in tumor immune surveillance. AREAS COVERED While NKG2D detect for potentially dangerous cells, various inhibitory and/or escape mechanisms counteract immune surveillance system and thereby limit effective elimination of transformed tumor cells. In addition, tumors often generate an immunosuppressive microenvironment where inhibitory molecules or cytokines negatively effect the function of anti-tumor immune responses. NKG2D ligand expression can be up-regulated by transcriptional or posttranscriptional mechanisms, therefore, certain therapy targeting those regulatory mechanisms could regain the expression of NKG2D ligands on tumor cells to be detected by the host immune responses. EXPERT OPINION Our knowledge in the precise mechanism of anti-tumor immunity is rapidly increasing. While NKG2D is known as primary cytotoxicity receptor in NK cell activation by recognizing 'induced-self' ligands on stressed cells including tumor cells, there are increasing evidences that NKG2D recognition can result in both immune activation and immune silencing. Future combined application of conventional cancer therapy and new therapy utilizing such stress-induced recognition systems will provide a novel opportunity to control malignant tumor progression of cancer disease.
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Affiliation(s)
- Yoshihiro Hayakawa
- The University of Tokyo, Graduate School of Pharmaceutical Sciences, Laboratory of Cancer Biology and Molecular Immunology, Bunkyo-ku, Japan.
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Saether PC, Hoelsbrekken SE, Fossum S, Dissen E. Rat and Mouse CD94 Associate Directly with the Activating Transmembrane Adaptor Proteins DAP12 and DAP10 and Activate NK Cell Cytotoxicity. THE JOURNAL OF IMMUNOLOGY 2011; 187:6365-73. [DOI: 10.4049/jimmunol.1102345] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
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Cheung R, Shen F, Phillips JH, McGeachy MJ, Cua DJ, Heyworth PG, Pierce RH. Activation of MDL-1 (CLEC5A) on immature myeloid cells triggers lethal shock in mice. J Clin Invest 2011; 121:4446-61. [PMID: 22005300 DOI: 10.1172/jci57682] [Citation(s) in RCA: 49] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2011] [Accepted: 08/26/2011] [Indexed: 12/11/2022] Open
Abstract
Systemic inflammatory response syndrome (SIRS) is a potentially lethal condition, as it can progress to shock, multi-organ failure, and death. It can be triggered by infection, tissue damage, or hemorrhage. The role of tissue injury in the progression from SIRS to shock is incompletely understood. Here, we show that treatment of mice with concanavalin A (ConA) to induce liver injury triggered a G-CSF-dependent hepatic infiltration of CD11b+Gr-1+Ly6G+Ly6C+ immature myeloid cells that expressed the orphan receptor myeloid DAP12-associated lectin-1 (MDL-1; also known as CLEC5A). Activation of MDL-1 using dengue virus or an agonist MDL-1-specific antibody in the ConA-treated mice resulted in shock. The MDL-1+ cells were pathogenic, and in vivo depletion of MDL-1+ cells provided protection. Triggering MDL-1 on these cells induced production of NO and TNF-α, which were found to be elevated in the serum of treated mice and required for MDL-1-induced shock. Surprisingly, MDL-1-induced NO and TNF-α production required eNOS but not iNOS. Activation of DAP12, DAP10, Syk, PI3K, and Akt was critical for MDL-1-induced shock. In addition, Akt physically interacted with and activated eNOS. Therefore, triggering of MDL-1 on immature myeloid cells and production of NO and TNF-α may play a critical role in the pathogenesis of shock. Targeting the MDL-1/Syk/PI3K/Akt/eNOS pathway represents a potential new therapeutic strategy to prevent the progression of SIRS to shock.
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Affiliation(s)
- Ricky Cheung
- Discovery Research, Merck Research Laboratories, Palo Alto, California, USA.
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Rajasekaran K, Chu H, Kumar P, Xiao Y, Tinguely M, Samarakoon A, Kim TW, Li X, Thakar MS, Zhang J, Malarkannan S. Transforming growth factor-beta-activated kinase 1 regulates natural killer cell-mediated cytotoxicity and cytokine production. J Biol Chem 2011; 286:31213-24. [PMID: 21771792 DOI: 10.1074/jbc.m111.261917] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Carma1, a caspase recruitment domain-containing membrane-associated guanylate kinase, initiates a unique signaling cascade via Bcl10 and Malt1 in NK cells. Carma1 deficiency results in reduced phosphorylation of JNK1/2 and activation of NF-κB that lead to impaired NK cell-mediated cytotoxicity and cytokine production. However, the precise identities of the downstream signaling molecules that link Carma1 to these effector functions were not defined. Here we show that transforming growth factor-β (TGF-β)-activated kinase 1 (TAK1) is abundantly present in NK cells, and activation via NKG2D results in its phosphorylation. Lack of Carma1 considerably reduced TAK1 phosphorylation, demonstrating the dependence of TAK1 on Carma1 in NKG2D-mediated NK cell activations. Pharmacological inhibitor to TAK1 significantly reduced NK-mediated cytotoxicity and its potential to generate IFN-γ, GM-CSF, MIP-1α, MIP-1β, and RANTES. Conditional in vivo knockdown of TAK1 in NK cells from Mx1Cre(+)TAK1(fx/fx) mice resulted in impaired NKG2D-mediated cytotoxicity and cytokine/chemokine production. Inhibition or conditional knockdown of TAK1 severely impaired the NKG2D-mediated phosphorylation of ERK1/2 and JNK1/2 and activation of NF-κB and AP1. Our results show that TAK1 links Carma1 to NK cell-mediated effector functions.
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Affiliation(s)
- Kamalakannan Rajasekaran
- Laboratory of Molecular Immunology and Immunotherapy, Blood Research Institute, Medical College of Wisconsin, Milwaukee, Wisconsin 53226, USA
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42
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Functions of skin-resident γδ T cells. Cell Mol Life Sci 2011; 68:2399-408. [PMID: 21560071 DOI: 10.1007/s00018-011-0702-x] [Citation(s) in RCA: 109] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2011] [Revised: 04/19/2011] [Accepted: 04/20/2011] [Indexed: 12/15/2022]
Abstract
The murine epidermis contains resident T cells that express a canonical γδ TCR and arise from fetal thymic precursors. These cells are termed dendritic epidermal T cells (DETC) and use a TCR that is restricted to the skin in adult animals. DETC produce low levels of cytokines and growth factors that contribute to epidermal homeostasis. Upon activation, DETC can secrete large amounts of inflammatory molecules which participate in the communication between DETC, neighboring keratinocytes and langerhans cells. Chemokines produced by DETC may recruit inflammatory cells to the epidermis. In addition, cell-cell mediated immune responses also appear important for epidermal-T cell communication. Information is provided which supports a crucial role for DETC in inflammation, wound healing, and tumor surveillance.
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Kerr WG, Colucci F. Inositol phospholipid signaling and the biology of natural killer cells. J Innate Immun 2011; 3:249-57. [PMID: 21422750 DOI: 10.1159/000323920] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2010] [Accepted: 12/07/2010] [Indexed: 12/30/2022] Open
Abstract
A family of phosphoinositide-3 kinase (PI3K) isoenzymes catalyzes the production of second messengers that recruit critical regulators of cell growth, survival, proliferation and motility. Conversely, 3'-(phosphatase and tensin homolog) and 5'-inositol polyphosphatases (SH2-containing inositol phosphatases 1/2, SHIP1/2) are recruited to sites of PI3K signaling at the plasma membrane to oppose or, in some cases, to modify and enhance PI3K signaling. A substantial and growing body of literature demonstrates that these enzymes which mediate interchange of phosphates on inositol phospholipid species at the plasma membrane have prominent roles in natural killer cell biology, including development, effector functions and trafficking. Here, we review the salient points of these recent papers with a special emphasis on the role of p110δ and SHIP1 in natural killer cells.
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Affiliation(s)
- William G Kerr
- Department of Microbiology and Immunology, SUNY Upstate Medical University, Syracuse, NY 13210, USA.
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44
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Engels N, Wienands J. The signaling tool box for tyrosine-based costimulation of lymphocytes. Curr Opin Immunol 2011; 23:324-9. [PMID: 21324660 DOI: 10.1016/j.coi.2011.01.005] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2011] [Accepted: 01/24/2011] [Indexed: 12/31/2022]
Abstract
Triggering lymphocyte effector functions is controlled by a diverse array of immune cell coreceptors that dampen or potentiate the primary activation signal from antigen receptors. Attenuation of lymphocyte activation has been shown to be accomplished by immunoreceptor tyrosine-based inhibition motifs that upon phosphorylation recruit protein or lipid phosphatases. By contrast, a general concept of signal amplification and/or diversification is still out. However, the recent discovery of antigen receptor-intrinsic costimulation by membrane-bound immunoglobulins in class-switched memory B cells identified a consensus phosphorylation motif that can boost antigen-induced signal chains and is also employed by costimulatory receptors on T and Natural Killer cells to provide secondary signals for cellular activation. Here we define a common basis of tyrosine-based lymphocyte costimulation comprising immunoglobulin tail tyrosine (ITT)-like phosphorylation motifs and their proximal effectors, growth factor receptor-bound protein (Grb) 2 and phosphatidylinositol-3 kinase (PI3K) enzymes of class IA.
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Affiliation(s)
- Niklas Engels
- Georg August University of Göttingen, Institute of Cellular and Molecular Immunology, Humboldtallee 34, 37073 Göttingen, Germany
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45
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Ogbomo H, Biru T, Michaelis M, Loeschmann N, Doerr HW, Cinatl J. The anti-tumoral drug enzastaurin inhibits natural killer cell cytotoxicity via activation of glycogen synthase kinase-3β. Biochem Pharmacol 2011; 81:251-8. [DOI: 10.1016/j.bcp.2010.09.026] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2010] [Revised: 09/06/2010] [Accepted: 09/28/2010] [Indexed: 01/18/2023]
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46
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Höglund P, Brodin P. Current perspectives of natural killer cell education by MHC class I molecules. Nat Rev Immunol 2010; 10:724-34. [PMID: 20818413 DOI: 10.1038/nri2835] [Citation(s) in RCA: 159] [Impact Index Per Article: 10.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
From the early days of natural killer (NK) cell research, it was clear that MHC genes controlled the specificity of mouse NK cell-dependent responses, such as the ability to reject transplanted allogeneic bone marrow and to kill tumour cells. Although several mechanisms that are involved in this 'education' process have been clarified, most of the mechanisms have still to be identified. Here, we review the current understanding of the processes that are involved in NK cell education, including how the host MHC class I molecules regulate responsiveness and receptor repertoire formation in NK cells and the signalling pathways that are involved.
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Affiliation(s)
- Petter Höglund
- Department of Microbiology, Tumour and Cell Biology, Karolinska Institutet, SE-171 77, Stockholm, Sweden
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47
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Watzl C, Long EO. Signal transduction during activation and inhibition of natural killer cells. CURRENT PROTOCOLS IN IMMUNOLOGY 2010; Chapter 11:Unit 11.9B. [PMID: 20814939 PMCID: PMC3857016 DOI: 10.1002/0471142735.im1109bs90] [Citation(s) in RCA: 91] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Abstract
Natural killer (NK) cells are important for early immune responses to viral infections and cancer. Upon activation, NK cells secrete cytokines and chemokines, and kill sensitive target cells by releasing the content of cytolytic granules. This unit is focused on the signal transduction pathways that regulate NK cell activities in response to contact with other cells. We will highlight signals regulating NK cell adhesion to target cells and describe the induction of cellular cytotoxicity by the engagement of different NK cell activation receptors. Negative signaling induced by inhibitory receptors opposes NK cell activation and provides an important safeguard from NK cell reactivity toward normal, healthy cells. We will discuss the complex integration of the different signals that occur during interaction of NK cells with target cells.
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Affiliation(s)
- Carsten Watzl
- Institute for Immunology, University Heidelberg, Heidelberg, Germany
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48
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Pegram HJ, Andrews DM, Smyth MJ, Darcy PK, Kershaw MH. Activating and inhibitory receptors of natural killer cells. Immunol Cell Biol 2010; 89:216-24. [PMID: 20567250 DOI: 10.1038/icb.2010.78] [Citation(s) in RCA: 375] [Impact Index Per Article: 25.0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
Natural killer (NK) cells are potent immune effector cells that can respond to infection and cancer, as well as allowing maternal adaptation to pregnancy. In response to malignant transformation or pathogenic invasion, NK cells can secrete cytokine and may be directly cytolytic, as well as exerting effects indirectly through other cells of the immune system. To recognize and respond to inflamed or infected tissues, NK cells express a variety of activating and inhibitory receptors including NKG2D, Ly49 or KIR, CD94-NKG2 heterodimers and natural cytotoxicity receptors, as well as co-stimulatory receptors. These receptors recognize cellular stress ligands as well as major histocompatibility complex class I and related molecules, which can lead to NK cell responses. Importantly, NK cells must remain tolerant of healthy tissue, and some of these receptors can also prevent activation of NK cells. In this review, we describe the expression of prominent NK cell receptors, as well as expression of their ligands and their role in immune responses. In addition, we describe the main signaling pathways used by NK cell receptors. Although we now appreciate that NK cell biology is more complicated than first thought, there are still facets of their biology that remain unclear. These will be highlighted and discussed in this review.
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Affiliation(s)
- Hollie J Pegram
- Cancer Immunology Research Program, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.
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Lee SH, Yun S, Piao ZH, Jeong M, Kim DO, Jung H, Lee J, Kim MJ, Kim MS, Chung JW, Kim TD, Yoon SR, Greenberg PD, Choi I. Suppressor of cytokine signaling 2 regulates IL-15-primed human NK cell function via control of phosphorylated Pyk2. THE JOURNAL OF IMMUNOLOGY 2010; 185:917-28. [PMID: 20543098 DOI: 10.4049/jimmunol.1000784] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
NK cells are capable of killing virus-infected or tumor cells and producing IFN-gamma. Resting NK cells, however, have only minimal cytolytic activity and secrete a low level of IFN-gamma. The cytokine IL-15 can promote the expression of effector functions by resting NK cells. In this study, we demonstrate that suppressor of cytokine signaling 2 (SOCS2) has a novel role in IL-15-primed human NK cell function. SOCS2 expression was upregulated in NK cells following stimulation with IL-15. During IL-15-mediated NK cell priming, SOCS2 interacted with phosphorylated proline-rich tyrosine kinase 2 (Pyk2) at tyrosine 402 (p-Pyk2(Tyr402)) and induced the proteasome-mediated degradation of p-Pyk2(Tyr402) via ubiquitination. Knockdown of SOCS2 resulted in the accumulation of p-Pyk2(Tyr402) and blocked NK cell effector functions. In addition, NK cell cytolytic activity and IFN-gamma production were inhibited by overexpression of the wild-type of Pyk2 but not by the overexpression of tyrosine 402 mutant of Pyk2. These results suggest that SOCS2 regulates human NK cell effector functions via control of phosphorylated Pyk2 depending on IL-15 existence.
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Affiliation(s)
- Suk Hyung Lee
- Cell Therapy Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, Republic of Korea
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Mócsai A, Ruland J, Tybulewicz VLJ. The SYK tyrosine kinase: a crucial player in diverse biological functions. Nat Rev Immunol 2010; 10:387-402. [PMID: 20467426 PMCID: PMC4782221 DOI: 10.1038/nri2765] [Citation(s) in RCA: 1018] [Impact Index Per Article: 67.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Spleen tyrosine kinase (SYK) is known to have a crucial role in adaptive immune receptor signalling. However, recent reports indicate that SYK also mediates other, unexpectedly diverse biological functions, including cellular adhesion, innate immune recognition, osteoclast maturation, platelet activation and vascular development. SYK is activated by C-type lectins and integrins, and activates new targets, including the CARD9-BCL-10-MALT1 pathway and the NLRP3 inflammasome. Studies using Drosophila melanogaster suggest that there is an evolutionarily ancient origin of SYK-mediated signalling. Moreover, SYK has a crucial role in autoimmune diseases and haematological malignancies. This Review summarizes our current understanding of the diverse functions of SYK and how this is being translated for therapeutic purposes.
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Affiliation(s)
- Attila Mócsai
- Department of Physiology, Semmelweis University School of Medicine, 1094 Budapest, Hungary.
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