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.

AttenuatedListeria monocytogenescarrier strains can deliver an HIV-1 gp120 T helper epitope to MHC class II-restricted human CD4+ T cells

1998 ◽  
Vol 28 (6) ◽  
pp. 1807-1814 ◽  
Author(s):  
Carlos A. Guzmán ◽  
Daniele Saverino ◽  
Eva Medina ◽  
Daniela Fenoglio ◽  
Birgit Gerstel ◽  
...  
Keyword(s):  
T Cells ◽  
Mhc Class Ii ◽  
Cd4 T Cells ◽  
Class Ii ◽  
T Helper ◽  
Helper Epitope ◽  
Hiv 1

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.

scholarly journals Discordance in the Epithelial Cell-Dendritic Cell Major Histocompatibility Complex Class II Immunoproteome: Implications for Chlamydia Vaccine Development

2019 ◽  
Vol 221 (5) ◽  
pp. 841-850
Author(s):  
Karuna P Karunakaran ◽  
Hong Yu ◽  
Xiaozhou Jiang ◽  
Queenie W T Chan ◽  
Leonard J Foster ◽  
...  
Keyword(s):  
T Cells ◽  
Major Histocompatibility Complex ◽  
Epithelial Cell ◽  
Epithelial Cells ◽  
Mhc Class Ii ◽  
Cd4 T Cells ◽  
Protective Immunity ◽  
Class Ii ◽  
Class I ◽  
Histocompatibility Complex

Abstract Background Chlamydia trachomatis and Chlamydia muridarum are intracellular bacterial pathogens of mucosal epithelial cells. CD4 T cells and major histocompatibility complex (MHC) class II molecules are essential for protective immunity against them. Antigens presented by dendritic cells (DCs) expand naive pathogen-specific T cells (inductive phase), whereas antigens presented by epithelial cells identify infected epithelial cells as targets during the effector phase. We previously showed that DCs infected by C trachomatis or C muridarum present epitopes from a limited spectrum of chlamydial proteins recognized by Chlamydia-specific CD4 T cells from immune mice. Methods We hypothesized that Chlamydia-infected DCs and epithelial cells present overlapping sets of Chlamydia-MHC class II epitopes to link inductive and effector phases to generate protective immunity. We tested that hypothesis by infecting an oviductal epithelial cell line with C muridarum, followed by immunoaffinity isolation and sequencing of MHC class I- and II-bound peptides. Results We identified 26 class I-bound and 4 class II-bound Chlamydia-derived peptides from infected epithelial cells. We were surprised to find that none of the epithelial cell class I- and class II-bound chlamydial peptides overlapped with peptides presented by DCs. Conclusions We suggest the discordance between the DC and epithelial cell immunoproteomes has implications for delayed clearance of Chlamydia and design of a Chlamydia vaccine.

scholarly journals Autoimmune diabetes can be induced in transgenic major histocompatibility complex class II-deficient mice.

1993 ◽  
Vol 178 (2) ◽  
pp. 589-596 ◽  
Author(s):  
T M Laufer ◽  
M G von Herrath ◽  
M J Grusby ◽  
M B Oldstone ◽  
L H Glimcher
Keyword(s):  
T Cells ◽  
Major Histocompatibility Complex ◽  
Mhc Class Ii ◽  
Cd4 T Cells ◽  
Islet Cells ◽  
Autoimmune Diabetes ◽  
Class Ii ◽  
Dependent Diabetes Mellitus ◽  
Major Histocompatibility ◽  
Histocompatibility Complex

Insulin-dependent diabetes mellitus (IDDM) is an autoimmune disease marked by hyperglycemia and mononuclear cell infiltration of insulin-producing beta islet cells. Predisposition to IDDM in humans has been linked to the class II major histocompatibility complex (MHC), and islet cells often become aberrantly class II positive during the course of the disease. We have used two recently described transgenic lines to investigate the role of class II molecules and CD4+ T cells in the onset of autoimmune insulitis. Mice that are class II deficient secondary to a targeted disruption of the A beta b gene were bred to mice carrying a transgene for the lymphocytic choriomenigitis virus (LCMV) glycoprotein (GP) targeted to the endocrine pancreas. Our results indicate that class II-deficient animals with and without the GP transgene produce a normal cytotoxic T lymphocyte response to whole LCMV. After infection with LCMV, GP-transgenic class II-deficient animals develop hyperglycemia as rapidly as their class II-positive littermates. Histologic examination of tissue sections from GP-transgenic class II-deficient animals reveals lymphocytic infiltrates of the pancreatic islets that are distinguishable from those of their class II-positive littermates only by the absence of infiltrating CD4+ T cells. These results suggest that in this model of autoimmune diabetes, CD4+ T cells and MHC class II molecules are not required for the development of disease.

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 How Do CD4+ T Cells Detect and Eliminate Tumor Cells That Either Lack or Express MHC Class II Molecules?

2014 ◽  
Vol 5 ◽  
Author(s):  
Ole Audun Werner Haabeth ◽  
Anders Aune Tveita ◽  
Marte Fauskanger ◽  
Fredrik Schjesvold ◽  
Kristina Berg Lorvik ◽  
...  
Keyword(s):  
T Cells ◽  
Tumor Cells ◽  
Mhc Class Ii ◽  
Cd4 T Cells ◽  
Class Ii ◽  
Mhc Class Ii Molecules

scholarly journals Quantitative Analysis of the T Cell Repertoire Selected by a Single Peptide–Major Histocompatibility Complex

1998 ◽  
Vol 187 (11) ◽  
pp. 1871-1883 ◽  
Author(s):  
Laurent Gapin ◽  
Yoshinori Fukui ◽  
Jean Kanellopoulos ◽  
Tetsuro Sano ◽  
Armanda Casrouge ◽  
...  
Keyword(s):  
T Cells ◽  
Major Histocompatibility Complex ◽  
T Cell ◽  
Mhc Class Ii ◽  
Cd4 T Cells ◽  
Class Ii ◽  
T Cell Repertoire ◽  
Cell Repertoire ◽  
Histocompatibility Complex ◽  
Single Peptide

The positive selection of CD4+ T cells requires the expression of major histocompatibility complex (MHC) class II molecules in the thymus, but the role of self-peptides complexed to class II molecules is still a matter of debate. Recently, it was observed that transgenic mice expressing a single peptide–MHC class II complex positively select significant numbers of diverse CD4+ T cells in the thymus. However, the number of selected T cell specificities has not been evaluated so far. Here, we have sequenced 700 junctional complementarity determining regions 3 (CDR3) from T cell receptors (TCRs) carrying Vβ11-Jβ1.1 or Vβ12-Jβ1.1 rearrangements. We found that a single peptide–MHC class II complex positively selects at least 105 different Vβ rearrangements. Our data yield a first evaluation of the size of the T cell repertoire. In addition, they provide evidence that the single Eα52-68–I-Ab complex skews the amino acid frequency in the TCR CDR3 loop of positively selected T cells. A detailed analysis of CDR3 sequences indicates that a fraction of the β chain repertoire bears the imprint of the selecting self-peptide.

scholarly journals Epithelial MHC class II directs microbiota-specific intestinal immune homeostasis

2022 ◽  
Author(s):  
Emily M Eshleman ◽  
Tzu-Yu Shao ◽  
Vivienne Woo ◽  
Taylor Rice ◽  
Jordan Whitt ◽  
...  
Keyword(s):  
T Cells ◽  
Mhc Class Ii ◽  
Cd4 T Cells ◽  
Intestinal Epithelial ◽  
Mhc Ii ◽  
Adult Mice ◽  
Histocompatibility Complex ◽  
Mucosal Tissues ◽  
T Cell Regulation ◽  
Antigen Presenting

Dysregulated immune responses to resident microbes promote pathologic inflammation, however, the mechanisms instructing commensal-specific T cells remain poorly understood. Here, we find that non-hematopoietic intestinal epithelial cells (IECs) represent the primary cells expressing major histocompatibility complex (MHC) II at the intestinal host-microbiota interface. Interestingly, epithelial MHCII and commensal-specific CD4+ T cells were concurrently induced by post-natal microbiota colonization, provoking the hypothesis that epithelial MHCII regulates local commensal-specific CD4+ T cells. While MHCII on classical antigen presenting cells directs expansion of antigen-specific CD4+ T cells, loss of IEC-intrinsic MHCII surprisingly led to elevated commensal-specific CD4+ T cells in the intestine. Further, epithelial MHCII expression actively limited accumulation of antigen-specific CD4+ T cells in adult mice. Expansion of commensal-specific Th17 cells was restricted by epithelial MHCII, and remarkably mice lacking epithelial MHCII were highly susceptible to microbiota-triggered inflammation. Collectively, these data indicate that impaired epithelial MHCII-T cell regulation within mucosal tissues alters microbiota-specific immunity and predisposes to chronic inflammation.

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 Survival of Mature CD4 T Lymphocytes Is Dependent on Major Histocompatibility Complex Class II–expressing Dendritic Cells

1997 ◽  
Vol 186 (8) ◽  
pp. 1223-1232 ◽  
Author(s):  
Thomas Brocker
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
Major Histocompatibility Complex ◽  
T Cell ◽  
Mhc Class Ii ◽  
Cd4 T Cells ◽  
Close Contact ◽  
Class Ii ◽  
Major Histocompatibility ◽  
Histocompatibility Complex

Thymic T cell development is controlled by T cell receptor (TCR)–major histocompatibility complex (MHC) interactions, whereas a further dependence of peripheral mature T cells on TCR–MHC contact has not been described so far. To study this question, CD4 T cell survival was surveyed in mice lacking MHC class II expression and in mice expressing MHC class II exclusively on dendritic cells. Since neither of these mice positively select CD4 T cells in the thymus, they were grafted with MHC class II–positive embryonic thymic tissue, which had been depleted of bone marrow derived cells. Although the thymus grafts in both hosts were repopulated with host origin thymocytes of identical phenotype and numbers, an accumulation of CD4+ T cells in peripheral lymphoid organs could only be observed in mice expressing MHC class II on dendritic cells, but not in mice that were completely MHC class II deficient. As assessed by histology, the accumulating peripheral CD4 T cells were found to be in close contact with MHC class II+ dendritic cells, suggesting that CD4 T cells need peripheral MHC class II expression for survival and that class II+ dendritic cells might play an important role for the longevity of CD4 T cells.

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