• CCL19
• CCL21
• GPR183
• cholesterol metabolites
• high endothelial venules
• lymph nodes
• lymphocyte trafficking
• stromal cells
• tumors
• viral infection

• Lymph Nodes/metabolism
• Animals
• Mice
• Receptors, CCR7/metabolism
• Inflammation/metabolism
• Inflammation/pathology
• Chemokine CCL19/metabolism
• Steroid Hydroxylases/metabolism
• Steroid Hydroxylases/genetics
• Mice, Inbred C57BL
• Humans
• Oxysterols/metabolism
• Cell Movement
• Chemokine CCL21/metabolism
• Lymphocytes/metabolism
• B-Lymphocytes/metabolism
• B-Lymphocytes/immunology
• Receptors, G-Protein-Coupled

• R01 AI040098 NIAID NIH HHS
• T32 GM007618 NIGMS NIH HHS
• R01 CA228019 NCI NIH HHS
• F32 CA200103 NCI NIH HHS
• R01 AI130471 NIAID NIH HHS
• I01 BX002919 BLRD VA
• F30 AI176727 NIAID NIH HHS
• R37 AI040098 NIAID NIH HHS

• C-C Chemokine Receptor 7
• antagonist
• integrin

• Receptors, CCR7/metabolism
• Receptors, CCR7/genetics
• Animals
• Humans
• Mice
• Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/metabolism
• Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/pathology
• Chemokine CCL19/metabolism
• CD18 Antigens/metabolism
• Central Nervous System/metabolism
• Central Nervous System/pathology
• Cell Line, Tumor
• Chemotaxis/drug effects
• Chemokine CCL21/metabolism
• Cell Movement/drug effects
• Neoplasm Invasiveness

• R03 CA270815 NCI NIH HHS
• U54 MD007592 NIMHD NIH HHS
• RO3 CA270815 NIH HHS

• A2BAR
• M1/M2
• MRS1754
• adenosine
• diabetic nephropathy
• macrophages
• monocytes
• polarization

• 11230660 FONDECYT
• 3180749 FONDECYT
• 1211613 FONDECYT

C-C chemokine receptor 7 (CCR7) was one of the first two chemokine receptors that were found to be upregulated in breast cancers. Chemokine receptors promote chemotaxis of cells and tissue organization. Since under homeostatic conditions, CCR7 promotes migration of immune cells to lymph nodes, questions immediately arose regarding the ability of CCR7 to direct migration of cancer cells to lymph nodes. The literature since 2000 was examined to determine to what extent the expression of CCR7 in malignant tumors promoted migration to the lymph nodes. The data indicated that in different cancers, CCR7 plays distinct roles in directing cells to lymph nodes, the skin or to the central nervous system. In certain tumors, it may even serve a protective role. Future studies should focus on defining mechanisms that differentially regulate the unfavorable or beneficial role that CCR7 plays in cancer pathophysiology, to be able to improve outcomes in patients who harbor CCR7-positive cancers.

• C-C chemokine receptor 7
• cancer
• metastases
• survival

Chemotactic factors locally secreted from tissues regulate leukocyte migration via cell membrane receptors that induce intracellular signals. It has been suggested that neutrophils stimulated by bacterial peptides secrete a secondary stimulant that enhances the chemotactic cell migration of the surrounding cells. This paracrine mechanism contributes to chemokine-dependent neutrophil migration, however, it has not yet been extensively studied in lymphocytes. In this study, we provide evidence that lymphocytes stimulated by the chemokine, CXCL12, affect the CXCR4-independent chemotactic response of the surrounding cells. We found that CXCR4-expressing lymphocytes or the conditioned medium from CXCL12-stimulated cells promoted CXCR4-deficient cell chemotaxis. In contrast, the conditioned medium from CXCL12-stimulated cells suppressed CCR7 ligand-dependent directionality and the cell migration speed of CXCR4-deficient cells. These results suggest that paracrine factors from CXCL12-stimulated cells navigate surrounding cells to CXCL12 by controlling the responsiveness to CCR7 ligand chemokines and CXCL12.

●

CXCL12-stimulated lymphocytes affect the CXCR4-independent chemotactic response of the surrounding cells.

• CXCR4
• Chemokine
• Chemotaxis
• Lymphocyte
• Migration
• Neutrophil

• Pancreatitis
• chemokines
• cytokines
• immune cell infiltration
• inflammation signaling
• pancreatic cancer

Foot‐and‐mouth disease (FMD) is a highly contagious, economically devastating disease of cloven‐hooved animals. The development of long‐lasting effective FMD vaccines would greatly benefit the global FMD control programme. Deep analysis of adaptive immunity in cattle vaccinated against FMD is technically challenging due to the lack of species‐specific tools. In this study, we aimed to identify CD4⁺ T‐cell epitopes in the FMD virus (FMDV) capsid and to phenotype the CD4⁺ T cells that recognize them using bovine major histocompatibility complex (BoLA) class II tetramer. A BoLA class II tetramer based on the DRA/DRB3*020:02 allele and FMDV antigen‐stimulated PBMCs from bovine vaccinates were used to successfully identify four epitopes in the FMDV capsid, three of which have not been previously reported; two epitopes were identified in the structural protein VP1, one in VP3 and one in VP4. Specificity of the three novel epitopes was confirmed by proliferation assay. All epitope‐expanded T‐cell populations produced IFN‐γ in vitro, indicating a long‐lasting Th1 cell phenotype after FMD vaccination. VP3‐specific CD4⁺ T cells exhibited the highest frequency amongst the identified epitopes, comprising >0·004% of the CD4⁺ T‐cell population. CD45RO⁺CCR7⁺ defined central memory CD4⁺ T‐cell subpopulations were present in higher frequency in FMDV‐specific CD4⁺ T‐cell populations from FMD‐vaccinated cattle ex vivo. This indicates an important role in maintaining cell adaptive immunity after FMD vaccination. Notably, FMDV epitope‐loaded tetramers detected the presence of FMDV‐specific CD4⁺ T cells in bovine PBMC more than four years after vaccination. This work contributes to our understanding of vaccine efficacy.

• foot-and-mouth disease vaccine
• memory T cell
• tetramer

The lymphatic system plays crucial roles in immunity far beyond those of simply providing conduits for leukocytes and antigens in lymph fluid. Endothelial cells within this vasculature are distinct and highly specialized to perform roles based upon their location. Afferent lymphatic capillaries have unique intercellular junctions for efficient uptake of fluid and macromolecules, while expressing chemotactic and adhesion molecules that permit selective trafficking of specific immune cell subsets. Moreover, in response to events within peripheral tissue such as inflammation or infection, soluble factors from lymphatic endothelial cells exert “remote control” to modulate leukocyte migration across high endothelial venules from the blood to lymph nodes draining the tissue. These immune hubs are highly organized and perfectly arrayed to survey antigens from peripheral tissue while optimizing encounters between antigen-presenting cells and cognate lymphocytes. Furthermore, subsets of lymphatic endothelial cells exhibit differences in gene expression relating to specific functions and locality within the lymph node, facilitating both innate and acquired immune responses through antigen presentation, lymph node remodeling and regulation of leukocyte entry and exit. This review details the immune cell subsets in afferent and efferent lymph, and explores the mechanisms by which endothelial cells of the lymphatic system regulate such trafficking, for immune surveillance and tolerance during steady-state conditions, and in response to infection, acute and chronic inflammation, and subsequent resolution.

• T-cell
• adhesion molecule
• chemokine
• dendritic cell
• high endothelial venule
• inflammation
• lymph node
• lymphatic
• migration
• trafficking

• Biased agonism
• Chemokine System
• G protein-coupled receptors

Transplantation of cardiomyocytes derived from induced pluripotent stem cell (iPSC-CMs) is a promising approach for increasing functional CMs during end-stage heart failure. Although major histocompatibility complex (MHC) class I matching between donor cells and recipient could reduce acquired immune rejection, innate immune responses may have negative effects on transplanted iPSC-CMs. Here, we demonstrated that natural killer cells (NKCs) infiltrated in iPSC-CM transplants even in a syngeneic mouse model. The depletion of NKCs using an anti-NKC antibody rescued transplanted iPSC-CMs, suggesting that iPSC-CMs activated NKC-mediated innate immunity. Surprisingly, iPSC-CMs lost inhibitory MHCs but not activating ligands for NKCs. Re-expression of MHC class I induced by IFN-γ as well as suppression of activating ligands by an antibody rescued the transplanted iPSC-CMs. Thus, NKCs impede the engraftment of transplanted iPSC-CMs because of lost MHC class I, and our results provide a basis for an approach to improve iPSC-CM engraftment.

• Adult
• Animals
• Cardiovascular Diseases/metabolism
• Child
• Humans
• Hypertension/metabolism
• Risk Factors
• Stress, Psychological/metabolism

• P01 HL069999 NHLBI NIH HHS
• T32 DK007545 NIDDK NIH HHS

• Bone marrow
• CXCL12
• CXCR3
• CXCR4
• Migration
• T cells
• stromal cells

• Antigens, CD1/genetics
• Antigens, CD1/immunology
• Blood Cells/immunology
• CD5 Antigens/analysis
• CD5 Antigens/genetics
• Cell Differentiation/drug effects
• Chemokine CCL21/pharmacology
• Dendritic Cells/classification
• Dendritic Cells/drug effects
• Dendritic Cells/immunology
• Dendritic Cells/physiology
• Glycoproteins/genetics
• Glycoproteins/immunology
• Humans
• Immune Tolerance
• Interferon Regulatory Factors/genetics
• Interferon Regulatory Factors/immunology
• Interleukin-10/immunology
• Interleukin-4/biosynthesis
• Interleukin-4/immunology
• Interleukins/biosynthesis
• Interleukins/immunology
• Lymphocyte Activation
• Phenotype
• T-Lymphocytes, Helper-Inducer/immunology
• T-Lymphocytes, Regulatory/immunology
• Th1 Cells/immunology
• Interleukin-22

Multiple sclerosis (MS) is a T cell-mediated autoimmune disease. Fingolimod, a highly effective disease-modifying drug for MS, retains CCR7⁺ central memory T cells in which autoaggressive T cells putatively exist, in secondary lymphoid organs, although relapse may still occur in some patients. Here, we analyzed the T cell phenotypes of fingolimod-treated, fingolimod-untreated patients, and healthy subjects. The frequency of CD56⁺ T cells and granzyme B-, perforin-, and Fas ligand-positive T cells significantly increased during fingolimod treatment. Each T cell subpopulation further increased during relapse. Interestingly, T cells from fingolimod-treated patients exhibited interferon-γ biased production, and more myelin basic protein-reactive cells was noted in CD56⁺ than in CD56⁻ T cells. It is likely that the altered T cell phenotypes play a role in MS relapse in fingolimod-treated patients. Further clinical studies are necessary to investigate whether altered T cell phenotypes are a biomarker for relapse under fingolimod therapy.

• angiogenesis
• chemokine receptors
• chemokines
• lymphangiogenesis
• pancreatic neoplasms

• adventitia
• aorta
• flow cytometer
• hypertension
• inflammation

• Air pouch
• Chemokine
• Chemokine receptor
• Chemotactic gradient
• Diffusion gradient chemotaxis
• Glycosaminoglycans
• In vivo chemotaxis
• Stable transfectants
• Transendothelial chemotaxis

• ELISPOT
• Memory markers
• Mycobacteria
• T-cells
• Tuberculosis

• Cell migration
• Dendritic cell vaccine
• Imiquimod cream
• Lymph node homing
• Melanoma
• Standard cytokine cocktail

• Aminoquinolines/pharmacology
• Animals
• Cancer Vaccines/immunology
• Cell Movement
• Chemotaxis
• Cytokines/physiology
• Dendritic Cells/immunology
• Humans
• Imiquimod
• Lymph Nodes/immunology
• Matrix Metalloproteinase 9/metabolism
• Melanoma/immunology
• Melanoma/pathology
• Mice
• Mice, Nude
• Neoplasm Invasiveness
• T-Lymphocytes/immunology

During human immunodeficiency virus (HIV) infection, enhanced migration of infected cells to lymph nodes leads to efficient propagation of HIV-1. The selective chemokine receptors, including CXCR4 and CCR7, may play a role in this process, yet the viral factors regulating chemokine-dependent T cell migration remain relatively unclear. The functional cooperation between the CXCR4 ligand chemokine CXCL12 and the CCR7 ligand chemokines CCL19 and CCL21 enhances CCR7-dependent T cell motility in vitro as well as cell trafficking into the lymph nodes in vivo. In this study, we report that a recombinant form of a viral CXCR4 ligand, X4-tropic HIV-1 gp120, enhanced the CD4 T cell response to CCR7 ligands in a manner dependent on CXCR4 and CD4, and that this effect was recapitulated by HIV-1 virions. HIV-1 gp120 significantly enhanced CCR7-dependent CD4 T cell migration from the footpad of mice to the draining lymph nodes in in vivo transfer experiments. We also demonstrated that CXCR4 expression is required for stable CCR7 expression on the CD4 T cell surface, whereas CXCR4 signaling facilitated CCR7 ligand binding to the cell surface and increased the level of CCR7 homo- as well as CXCR4/CCR7 hetero-oligomers without affecting CCR7 expression levels. Our findings indicate that HIV-evoked CXCR4 signaling promotes CCR7-dependent CD4 T cell migration by up-regulating CCR7 function, which is likely to be induced by increased formation of CCR7 homo- and CXCR4/CCR7 hetero-oligomers on the surface of CD4 T cells.

• Animals
• CD4-Positive T-Lymphocytes/cytology
• CD4-Positive T-Lymphocytes/immunology
• Cell Movement/drug effects
• Chemokine CCL21/pharmacology
• HIV Envelope Protein gp120/genetics
• HIV Envelope Protein gp120/metabolism
• HIV Envelope Protein gp120/pharmacology
• HIV-1/metabolism
• Humans
• Ligands
• Mice
• Mice, Inbred C57BL
• Protein Multimerization
• RNA Interference
• RNA, Small Interfering/metabolism
• Receptors, CCR7/antagonists & inhibitors
• Receptors, CCR7/genetics
• Receptors, CCR7/metabolism
• Receptors, CXCR4/genetics
• Receptors, CXCR4/metabolism
• Recombinant Proteins/biosynthesis
• Recombinant Proteins/genetics
• Recombinant Proteins/pharmacology
• Signal Transduction/drug effects
• Up-Regulation/drug effects
• Virion/physiology

Leukemia is a systemic malignancy originated from hematopoietic cells. The extracellular environment has great impacts on the survival, proliferation and dissemination of leukemia cells. The spleen is an important organ for extramedullary hematopoiesis and a common infiltration site in lymphoid malignancies. Splenomegaly, frequently observed in T cell acute lymphoblastic leukemia (T-ALL), is associated with poor prognosis. However, how the spleen microenvironment distinctly affects T-ALL cells as opposed to bone marrow (BM) microenvironment has not been addressed.

A Notch1-induced mouse T-ALL model was applied in this study. Flow cytometry and two-photon fluorescence microscopy were used to analyze early distribution of T-ALL cells. MILLIPLEX® MAP Multiplex Immunoassay was performed to measure cytokine/chemokine levels in different microenvironments. Transwell and co-culture experiments were used to test the effects of splenic microenvironment in vitro. Splenectomy was performed to assess the organ specific impact on the survival of T-ALL-bearing mice.

More leukemia cells were detected in the spleen than in the BM after injection of T-ALL cells by flow cytometry and two-photon fluorescence microscopy analysis. By screening a panel of cytokines/chemokines, a higher level of MIP-3β was found in the splenic microenvironment than BM microenvironment. In vitro transwell experiment further confirmed that MIP-3β recruits T-ALL cells which express a high level of MIP-3β receptor, CCR7. Furthermore, the splenic microenvironment stimulates T-ALL cells to express a higher level of MIP-3β, which further recruits T-ALL cells to the spleen. Co-culture experiment found that the splenic microenvironment more potently stimulated the proliferation and migration of T-ALL cells than BM. Moreover, the mice transplanted with T-ALL cells from the spleen had a shorter life span than those transplanted from BM, suggesting increased potency of the T-ALL cells induced by the splenic microenvironment. In addition, splenectomy prolonged the survival of leukemic mice.

Our study demonstrates an organ specific effect on leukemia development. Specifically, T-ALL cells can be potentiated by splenic microenvironment and thus spleen may serve as a target organ for the treatment of some types of leukemia.

The online version of this article (doi:10.1186/s13045-014-0071-7) contains supplementary material, which is available to authorized users.

• Animals
• Arthropod Proteins/genetics
• Arthropod Proteins/metabolism
• Humans
• Protozoan Proteins/genetics
• Protozoan Proteins/metabolism
• Receptors, Chemokine/classification
• Receptors, Chemokine/genetics
• Receptors, Chemokine/metabolism
• Terminology as Topic
• Ticks
• Viral Proteins/genetics
• Viral Proteins/metabolism

• G0901113 Medical Research Council
• R37 AI040618 NIAID NIH HHS
• G0802838 Medical Research Council
• 099251 Wellcome Trust
• Intramural NIH HHS

• Infection
• Poxviridae infections
• Smallpox vaccine
• Vaccinia virus
• Zoonoses

• recombinant adeno-associated virus
• secondary lymphoid tissue chemokine
• anti-tumor effect
• tregs

• Animals
• Antineoplastic Agents/metabolism
• Cell Line, Tumor
• Chemokine CCL21/metabolism
• Dendritic Cells/metabolism
• Dependovirus/metabolism
• Female
• Flow Cytometry
• Forkhead Transcription Factors/metabolism
• Genetic Vectors/metabolism
• Immunohistochemistry
• Interleukin-2 Receptor alpha Subunit/metabolism
• Mice
• Mice, Inbred C57BL
• Mice, Nude
• T-Lymphocytes, Regulatory/drug effects
• T-Lymphocytes, Regulatory/immunology
• Transduction, Genetic

Beyond midlife, the immune system shows aging features and its defensive capability becomes impaired, by a process known as immunosenescence that involves many changes in the innate and adaptive responses. Innate immunity seems to be better preserved globally, while the adaptive immune response exhibits profound age-dependent modifications. Elderly people display a decline in numbers of naïve T-cells in peripheral blood and lymphoid tissues, while, in contrast, their proportion of highly differentiated effector and memory T-cells, such as the CD28^null T-cells, increases markedly. Naïve and memory CD4+ T-cells constitute a highly dynamic system with constant homeostatic and antigen-driven proliferation, influx, and loss of T-cells. Thymic activity dwindles with age and essentially ceases in the later decades of life, severely constraining the generation of new T-cells. Homeostatic control mechanisms are very effective at maintaining a large and diverse subset of naïve CD4+ T-cells throughout life, but although later than in CD8 + T-cell compartment, these mechanisms ultimately fail with age.

• CMV
• IL-15
• NKRs
• T-cells
• immunosenescence
• inflammation

T cell trafficking between the blood and lymphoid organs is a complex, multistep process that requires several highly dynamic and coordinated changes in cyto-architecture. Members of the ezrin, radixin and moesin (ERM) family of actin-binding proteins have been implicated in several aspects of this process, but studies have yielded conflicting results. Using mice with a conditional deletion of ezrin in CD4+ cells and moesin-specific siRNA, we generated T cells lacking ERM proteins, and investigated the effect on specific events required for T cell trafficking. ERM-deficient T cells migrated normally in multiple in vitro and in vivo assays, and could undergo efficient diapedesis in vitro. However, these cells were impaired in their ability to adhere to the β1 integrin ligand fibronectin, and to polarize appropriately in response to fibronectin and VCAM-1 binding. This defect was specific for β1 integrins, as adhesion and polarization in response to ICAM-1 were normal. In vivo, ERM-deficient T cells showed defects in homing to lymphoid organs. Taken together, these results show that ERM proteins are largely dispensable for T cell chemotaxis, but are important for β1 integrin function and homing to lymphoid organs.

• Animals
• Cell Adhesion/genetics
• Chemotaxis/genetics
• Chemotaxis/immunology
• Cytoskeletal Proteins/genetics
• Cytoskeletal Proteins/metabolism
• Integrin beta1/metabolism
• Ligands
• Lymphoid Tissue/immunology
• Lymphoid Tissue/metabolism
• Mice
• Mice, Transgenic
• Microfilament Proteins/deficiency
• Microfilament Proteins/genetics
• Microfilament Proteins/metabolism
• Receptors, CCR7/metabolism
• T-Lymphocytes/immunology
• T-Lymphocytes/metabolism
• Transendothelial and Transepithelial Migration/ethics
• Transendothelial and Transepithelial Migration/genetics

• P01 CA093615 NCI NIH HHS
• P30 CA016520 NCI NIH HHS
• P01CA093615 NCI NIH HHS

• Amino Acid Sequence
• Animals
• Chemokine CCL21/chemistry
• Chemokine CCL21/genetics
• Chemokine CCL21/immunology
• Chemokine CCL21/metabolism
• Chemokines, CC/chemistry
• Chemokines, CC/genetics
• Chemokines, CC/immunology
• Chemokines, CC/metabolism
• Cloning, Molecular
• Embryo, Nonmammalian/metabolism
• Models, Molecular
• Molecular Sequence Data
• Oocytes/metabolism
• Phylogeny
• Sequence Alignment
• Thymus Gland/embryology
• Thymus Gland/metabolism
• Transcriptome
• Zebrafish/embryology
• Zebrafish/genetics
• Zebrafish/immunology
• Zebrafish/metabolism
• Zebrafish Proteins/chemistry
• Zebrafish Proteins/genetics
• Zebrafish Proteins/immunology
• Zebrafish Proteins/metabolism

The water/glycerol channel aquaporin-3 is required for chemokine-dependent T cell migration during immune responses.

Chemokine-dependent trafficking is indispensable for the effector function of antigen-experienced T cells during immune responses. In this study, we report that the water/glycerol channel aquaporin-3 (AQP3) is expressed on T cells and regulates their trafficking in cutaneous immune reactions. T cell migration toward chemokines is dependent on AQP3-mediated hydrogen peroxide (H₂O₂) uptake but not the canonical water/glycerol transport. AQP3-mediated H₂O₂ transport is essential for the activation of the Rho family GTPase Cdc42 and the subsequent actin dynamics. Coincidentally, AQP3-deficient mice are defective in the development of hapten-induced contact hypersensitivity, which is attributed to the impaired trafficking of antigen-primed T cells to the hapten-challenged skin. We therefore suggest that AQP3-mediated H₂O₂ uptake is required for chemokine-dependent T cell migration in sufficient immune response.

This issue of Frontiers in Immunologic Tolerance explores barriers to tolerance from a variety of views of cells, molecules, and processes of the immune system. Our laboratory has spent over a decade focused on the migration of the cells of the immune system, and dissecting the signals that determine how and where effector and suppressive regulatory T cells traffic from one site to another in order to reject or protect allografts. These studies have led us to a greater appreciation of the anatomic structure of the immune system, and the realization that the path taken by lymphocytes during the course of the immune response to implanted organs determines the final outcome. In particular, the structures, microanatomic domains, and the cells and molecules that lymphocytes encounter during their transit through blood, tissues, lymphatics, and secondary lymphoid organs are powerful determinants for whether tolerance is achieved. Thus, the understanding of complex cellular and molecular processes of tolerance will not come from “96-well plate immunology,” but from an integrated understanding of the temporal and spatial changes that occur during the response to the allograft. The study of the precise positioning and movement of cells in lymphoid organs has been difficult since it is hard to visualize cells within their three-dimensional setting; instead techniques have tended to be dominated by two-dimensional renderings, although advanced confocal and two-photon systems are changing this view. It is difficult to precisely modify key molecules and events in lymphoid organs, so that existing knockouts, transgenics, inhibitors, and activators have global and pleiotropic effects, rather than precise anatomically restricted influences. Lastly, there are no well-defined postal codes or tracking systems for leukocytes, so that while we can usually track cells from point A to point B, it is exponentially more difficult or even impossible to track them to point C and beyond. We believe this represents one of the fundamental barriers to understanding the immune system and devising therapeutic approaches that take into account anatomy and structure as major controlling principles of tolerance.

• lymph node
• structure
• tolerance

Dendritic cells (DCs) are the main inducers and regulators of cytotoxic T lymphocyte (CTL) responses against viruses and tumors. One checkpoint to avoid misguided CTL activation, which might damage healthy cells of the body, is the necessity for multiple activation signals, involving both antigenic as well as additional signals that reflect the presence of pathogens. DCs provide both signals when activated by ligands of pattern recognition receptors and “licensed” by helper lymphocytes. Recently, it has been established that such T cell licensing can be facilitated by CD4⁺ T helper cells (“classical licensing”) or by natural killer T cells (“alternative licensing”). Licensing regulates the DC/CTL cross-talk at multiple layers. Direct recruitment of CTLs through chemokines released by licensed DCs has recently emerged as a common theme and has a crucial impact on the efficiency of CTL responses. Here, we discuss recent advances in our understanding of DC licensing for cross-priming and implications for the temporal and spatial regulation underlying this process. Future vaccination strategies will benefit from a deeper insight into the mechanisms that govern CTL activation.

• NKT cells
• T cell activation
• antigen presentation
• chemokines
• costimulation
• dendritic cells

• CD8-Positive T-Lymphocytes/immunology
• Enzyme-Linked Immunosorbent Assay
• Humans
• Immunologic Memory
• L-Selectin/genetics
• L-Selectin/immunology
• L-Selectin/metabolism
• Lymphocyte Activation/immunology
• Lysosomal-Associated Membrane Protein 1/metabolism
• Melanoma/immunology
• Melanoma/metabolism
• Melanoma/pathology
• Tumor Cells, Cultured

• Intramural NIH HHS

• Adsorption
• Alginates/chemistry
• Alginates/metabolism
• Biocompatible Materials/chemistry
• Biocompatible Materials/metabolism
• Cells, Cultured
• Chemokine CCL19/chemistry
• Chemokine CCL19/metabolism
• Chemokine CCL21/chemistry
• Chemokine CCL21/metabolism
• Chemokine CXCL10/chemistry
• Chemokine CXCL10/metabolism
• Chemokine CXCL12/chemistry
• Chemokine CXCL12/metabolism
• Chemokines/chemistry
• Chemokines/metabolism
• Chemotactic Factors/chemistry
• Chemotactic Factors/metabolism
• Chemotaxis/physiology
• Drug Carriers/chemistry
• Drug Carriers/metabolism
• Glucuronic Acid/chemistry
• Glucuronic Acid/metabolism
• Hexuronic Acids/chemistry
• Hexuronic Acids/metabolism
• Humans
• Materials Testing
• Microspheres
• T-Lymphocytes/chemistry
• T-Lymphocytes/cytology
• T-Lymphocytes/metabolism

• R01 EB007280-03 NIBIB NIH HHS
• Howard Hughes Medical Institute
• R01 EB007280 NIBIB NIH HHS
• 1R01EB007280 NIBIB NIH HHS
• R01 EB007280-01 NIBIB NIH HHS
• R01 EB007280-02 NIBIB NIH HHS