CD4 + T cells cross‐compete for MHC class II‐restricted peptide antigen complexes on the surface of antigen presenting cells

2004 ◽  
Vol 82 (2) ◽  
pp. 103-111 ◽  
Author(s):  
John D Hayball ◽  
Bruce W S Robinson ◽  
Richard A Lake
Keyword(s):  
T Cells ◽  
Mhc Class Ii ◽  
Cd4 T Cells ◽  
Antigen Presenting Cells ◽  
Class Ii ◽  
Peptide Antigen ◽  
Antigen Presenting

C-Type Lectin Receptor Mediated Immune Recognition of ADAMTS13 Promotes HLA-DRB1*11 Dependent Presentation of CUB1-2 Derived Peptides by Dendritic Cells

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 196-196
Author(s):  
Nicoletta Sorvillo ◽  
Simon D van Haren ◽  
Wouter Pos ◽  
Eszter Herczenik ◽  
Rob Fijnheer ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
Mhc Class Ii ◽  
Cd4 T Cells ◽  
Antigen Presenting Cells ◽  
Class Ii ◽  
Immune Recognition ◽  
Dependent Manner ◽  
Sirna Silencing ◽  
Antigen Presenting

Abstract Abstract 196 ADAMTS13 is a plasma metalloproteinase that regulates platelet adhesion and aggregation by virtue of its ability to process newly released ultra-large von Willebrand factor (VWF) multimers on the surface of endothelial cells. Autoantibodies directed against ADAMTS13 prohibit the processing of VWF multimers initiating a rare and life-threatening disorder called acquired thrombotic thrombocytopenic purpura (TTP). HLA-DRB1*11 has recently been identified as a risk factor for acquired TTP. This finding implies that formation of autoantibodies towards ADAMTS13 depends on appropriate presentation of ADAMTS13 derived peptides to CD4+ T-cells by antigen presenting cells. Here, we investigate endocytosis of recombinant ADAMTS13 by immature monocyte-derived dendritic cells (iDCs) using flow cytometry and confocal microscopy. Upon incubation of fluorescently labeled-rADAMTS13 with DCs, a time- and concentration dependent uptake of ADAMTS13 was observed. Endocytosis of ADAMTS13 was completely blocked upon addition of EGTA and mannan. We subsequently explored involvement of C-type lectins (CLRs) in the uptake of ADAMTS13 using specific blocking antibodies and siRNA silencing. We found that ADAMTS13 endocytosis was significantly decreased in cells treated with a monoclonal antibody directed towards macrophage mannose receptor (MR). Furthermore siRNA silencing of MR reduced the uptake of ADAMTS13 by dendritic cells. In vitro binding studies revealed that ADAMTS13 interacts with the carbohydrate recognition domains of MR. These data show that ADAMTS13 is internalized by iDCs in a MR-dependent manner. Antigen presenting cells continuously process endogenous and exogenous antigens into small peptides that are loaded on MHC class I or MHC class II for presentation to T lymphocytes. We have recently developed a method to analyze HLA-DR-presented peptide repertoires of dendritic cells pulsed with antigen (van Haren et al., 2011). Here, we addressed which ADAMTS13-derived peptides were presented on MHC class II alleles of a panel of both HLA-DRB1*11 positive and negative donors. Compared to previous studies with model antigens only a limited number of ADAMTS13-derived peptides were presented on MHC class II. Inspection of peptide-profiles obtained from DRB1*11 positive individuals revealed that two antigenic “core” peptides derived from the CUB1-2 domains of ADAMTS13 were presented by a DR11-positive donor. In addition to these immuno-dominant peptides several other peptides were also presented although with a markedly reduced efficiency. Our findings show that DRB1*11 expressing antigen presenting cells preferentially present antigenic “core” peptides derived from the CUB1-2 domains of ADAMTS13. We hypothesize that functional presentation of these peptides on HLA-DRB1*11 contributes to the onset of acquired TTP by stimulating low affinity self-reactive CD4+ T cells that have escaped negative selection in the thymus. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Specific T Helper Cell Requirement for Optimal Induction of Cytotoxic T Lymphocytes against Major Histocompatibility Complex Class II Negative Tumors

1998 ◽  
Vol 187 (5) ◽  
pp. 693-702 ◽  
Author(s):  
Ferry Ossendorp ◽  
Erica Mengedé ◽  
Marcel Camps ◽  
Rian Filius ◽  
Cornelis J.M. Melief
Keyword(s):  
T Cells ◽  
Tumor Cells ◽  
Mhc Class Ii ◽  
Cd4 T Cells ◽  
Protective Immunity ◽  
Class Ii ◽  
T Helper ◽  
Histocompatibility Complex ◽  
Helper Epitope ◽  
Antigen Presenting

This study shows that induction of tumor-specific CD4+ T cells by vaccination with a specific viral T helper epitope, contained within a synthetic peptide, results in protective immunity against major histocompatibility complex (MHC) class II negative, virus-induced tumor cells. Protection was also induced against sarcoma induction by acutely transforming retrovirus. In contrast, no protective immunity was induced by vaccination with an unrelated T helper epitope. By cytokine pattern analysis, the induced CD4+ T cells were of the T helper cell 1 type. The peptide-specific CD4+ T cells did not directly recognize the tumor cells, indicating involvement of cross-priming by tumor-associated antigen-presenting cells. The main effector cells responsible for tumor eradication were identified as CD8+ cytotoxic T cells that were found to recognize a recently described immunodominant viral gag-encoded cytotoxic T lymphocyte (CTL) epitope, which is unrelated to the viral env-encoded T helper peptide sequence. Simultaneous vaccination with the tumor-specific T helper and CTL epitopes resulted in strong synergistic protection. These results indicate the crucial role of T helper cells for optimal induction of protective immunity against MHC class II negative tumor cells. Protection is dependent on tumor-specific CTLs in this model system and requires cross-priming of tumor antigens by specialized antigen-presenting cells. Thus, tumor-specific T helper epitopes have to be included in the design of epitope-based vaccines.

scholarly journals Major Histocompatibility Complex Class II–Positive Cortical Epithelium Mediates the Selection of Cd4+25+ Immunoregulatory T Cells

2001 ◽  
Vol 194 (4) ◽  
pp. 427-438 ◽  
Author(s):  
Steven J. Bensinger ◽  
Antonio Bandeira ◽  
Martha S. Jordan ◽  
Andrew J. Caton ◽  
Terri M. Laufer
Keyword(s):  
T Cells ◽  
Major Histocompatibility Complex ◽  
Mhc Class Ii ◽  
Antigen Presenting Cells ◽  
Class Ii ◽  
Histocompatibility Complex ◽  
Antigen Presenting ◽  
Immunoregulatory T Cells ◽  
Deficient Mice ◽  
Selection Of

CD4+25+ T cells are a unique population of immunoregulatory T cells which are critical for the prevention of autoimmunity. To address the thymic selection of these cells we have used two models of attenuated thymic deletion. In K14-Aβb mice, major histocompatibility complex (MHC) class II I-Ab expression is limited to thymic cortical epithelium and deletion by hematopoietic antigen-presenting cells does not occur. In H2-DMα–deficient mice, MHC class II molecules contain a limited array of self-peptides resulting in inefficient clonal deletion. We find that CD4+25+ T cells are present in the thymus and periphery of K14-Aβb and H2-DMα–deficient mice and, like their wild-type counterparts, suppress the proliferation of cocultured CD4+25− effector T cells. In contrast, CD4+25+ T cells from MHC class II–deficient mice do not suppress responder CD4+ T cells in vitro or in vivo. Thus, development of regulatory CD4+25+ T cells is dependent on MHC class II-positive thymic cortical epithelium. Furthermore, analysis of the specificities of CD4+25+ T cells in K14-Aβb and H2-DMα–deficient mice suggests that a subset of CD4+25+ T cells is subject to negative selection on hematopoietic antigen-presenting cells.

scholarly journals Host MHC class II+ antigen-presenting cells and CD4 cells are required for CD8-mediated graft-versus-leukemia responses following delayed donor leukocyte infusions

Blood ◽  
2006 ◽  
Vol 108 (6) ◽  
pp. 2106-2113 ◽  
Author(s):  
Ronjon Chakraverty ◽  
Hyeon-Seok Eom ◽  
Jessica Sachs ◽  
Jennifer Buchli ◽  
Pete Cotter ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Mhc Class Ii ◽  
Antigen Presenting Cells ◽  
Class Ii ◽  
Cd4 T Cell ◽  
Graft Versus Host ◽  
Graft Versus Leukemia ◽  
T Cell Help ◽  
Antigen Presenting

Abstract Following bone marrow transplantation, delayed donor leukocyte infusions (DLIs) can induce graft-versus-leukemia (GVL) effects without graft-versus-host disease (GVHD). These antitumor responses are maximized by the presence of host hematopoietic antigen-presenting cells (APCs) at the time of DLI. Using a tumor-protection model, we demonstrate here that GVL activity following administration of DLIs to established mixed chimeras is dependent primarily on reactivity to allogeneic MHC antigens rather than minor histocompatibility or tumor-associated antigens. CD8+ T-cell–dependent GVL responses against an MHC class II–negative tumor following delayed DLI require CD4+ T-cell help and are reduced significantly when host APCs lack MHC class II expression. CD4+ T cells primed by host APCs were required for maximal expansion of graft-versus-host reactive CD8+ T cells but not their synthesis of IFN-γ. In contrast, the GVL requirement for CD4+ T-cell help was bypassed almost completely when DLI was administered to freshly irradiated recipients, indicating that the host environment is a major factor influencing the cellular mechanisms of GVL.

Interleukin-7 Produced by Antigen Presenting Cells Regulates the Homeostatic Peripheral Expansion of Naive CD4 T Cells.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 1333-1333
Author(s):  
Martin Guimond ◽  
Rachelle G. Veenstra ◽  
David J. Grindler ◽  
Yongzi Cui ◽  
Risu Na ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Lymphocytes ◽  
Cd4 T Cells ◽  
Antigen Presenting Cells ◽  
Class Ii ◽  
Chimeric Mice ◽  
Interleukin 7 ◽  
Antigen Presenting ◽  
Peripheral Expansion

Abstract Interleukin-7 (IL-7) is the only cytokine demonstrated thus far to directly support the development and maintenance of naive T cells. Interleukin-7 is produced mainly by the stroma of lymphoid organs but also to a lesser extent by antigen presenting cells. Dynamic changes in the relative availability of IL-7 during lymphopenia support T cell homeostatic peripheral expansion (HPE). Whereas HPE is very efficient at reconstituting the pool of mature CD8 T lymphocytes, regeneration of CD4 T lymphocytes via HPE is more problematic and deficits in CD4 T lymphocytes persist for years in humans following lymphodepletion. We demonstrate that in mice, CD4+ T cells undergo substantially diminished HPE compared to CD8+ T cells during lymphopenia. We hypothesized that CD4+ T cells uniquely require both MHC Class II plus IL-7 for survival and expansion during lymphopenia and that the availability of these signals are limited by the availability of IL-7 producing APCs. Consistent with this hypothesis, studies performed in chimeric mice showed that cells derived from APCs, but not stromal cells, provided the endogenous IL-7 that is require for naive CD4+ T cell HPE. Furthermore, whereas systemic exposure to high levels of rhIL-7 did not induce efficient homeostatic peripheral expansion of CD4+ cells, in vivo modulation of Class II expressing cells by flt3 ligand promoted homeostatic expansion of CD4+ T cells. Surprisingly however, we found that APCs respond to elevated systemic IL-7 by diminishing production of IL-7, a loop mediated by IL-7Rα and Stat5. As a result, elevated systemic IL-7 levels present during lymphopenia paradoxically diminish the production of IL-7 by APCs and thereby diminish CD4 HPE. This was directly demonstrated by experiments wherein CD4+ HPE was dramatically augmented in chimeric mice generated such that bone marrow derived cells lacked IL7Rα or Stat5. This work demonstrates a critical role for APC derived IL-7 in CD4+ regeneration and provides a new paradigm for understanding why prolonged CD4+ lymphopenia occurs following T cell depletion in humans.

scholarly journals Ligation of MHC Class II Induces PKC-Dependent Clathrin-Mediated Endocytosis of MHC Class II

Cells ◽  
2020 ◽  
Vol 9 (8) ◽  
pp. 1810
Author(s):  
Kento Masaki ◽  
Yuhji Hiraki ◽  
Hiroka Onishi ◽  
Yuka Satoh ◽  
Paul A. Roche ◽  
...  
Keyword(s):  
T Cells ◽  
Mhc Class Ii ◽  
Cd4 T Cells ◽  
Surface Expression ◽  
Class Ii ◽  
Cellular Functions ◽  
Mhc Ii ◽  
Histocompatibility Complex ◽  
Class Ii Mhc ◽  
Antigen Presenting

In addition to antigen presentation to CD4+ T cells, aggregation of cell surface major histocompatibility complex class II (MHC-II) molecules induces signal transduction in antigen presenting cells that regulate cellular functions. We previously reported that crosslinking of MHC-II induced the endocytosis of MHC-II, which was associated with decreased surface expression levels in murine dendritic cells (DCs) and resulted in impaired activation of CD4+ T cells. However, the downstream signal that induces MHC-II endocytosis remains to be elucidated. In this study, we found that the crosslinking of MHC-II induced intracellular Ca2+ mobilization, which was necessary for crosslinking-induced MHC-II endocytosis. We also found that these events were suppressed by inhibitors of Syk and phospholipase C (PLC). Treatments with a phorbol ester promoted MHC-II endocytosis, whereas inhibitors of protein kinase C (PKC) suppressed crosslinking-induced endocytosis of MHC-II. These results suggest that PKC could be involved in this process. Furthermore, crosslinking-induced MHC-II endocytosis was suppressed by inhibitors of clathrin-dependent endocytosis. Our results indicate that the crosslinking of MHC-II could stimulate Ca2+ mobilization and induce the clathrin-dependent endocytosis of MHC-II in murine DCs.

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