Dissection of human allostimulatory determinants with cloned T cells: Stimulation inhibition by monoclonal antibodies TÜ22, 34, 36, 37, 39, 43, and 58 against distinct human MHC class II molecules

Initial adhesive contacts between T lymphocytes and dendritic cells (DCs) facilitate recognition of peptide-MHC complexes by the TCR. In this report, we studied the dynamic behavior of adhesion and Ag receptors on DCs during initial contacts with T-cells. Adhesion molecules LFA-1- and ICAM-1,3-GFP as well as MHC class II-GFP molecules were very rapidly concentrated at the DC contact area. Binding of ICAM-3, and ICAM-1 to a lesser extent, to LFA-1 expressed by mature but not immature DC, induced MHC-II clustering into the immune synapse. Also, ICAM-3 binding to DC induced the activation of the Vav1-Rac1 axis, a regulatory pathway involved in actin cytoskeleton reorganization, which was essential for MHC-II clustering on DCs. Our results support a model in which ICAM-mediated MHC-II clustering on DC constitutes a priming mechanism to enhance antigen presentation to T-cells.

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Major histocompatibility complex-restricted recognition of retroviral superantigens by V beta 17+ T cells.

Journal of Experimental Medicine ◽

10.1084/jem.176.1.275 ◽

1992 ◽

Vol 176 (1) ◽

pp. 275-280 ◽

Cited By ~ 15

Author(s):

M A Blackman ◽

F E Lund ◽

S Surman ◽

R B Corley ◽

D L Woodland

Keyword(s):

T Cells ◽

Major Histocompatibility Complex ◽

Mhc Class Ii ◽

Class Ii ◽

Major Histocompatibility ◽

Direct Role ◽

Histocompatibility Complex ◽

Class Ii Mhc ◽

Mhc Class Ii Molecules

It has been established that at least some V beta 17+ T cells interact with an endogenous superantigen encoded by the murine retrovirus, Mtv-9. To analyze the role of major histocompatibility complex (MHC) class II molecules in presenting the Mtv-9 encoded superantigen, vSAG-9 to V beta 17+ hybridomas, a panel of nine hybridomas was tested for their ability to respond to A20/2J (H-2d) and LBK (H-2a) cells which had been transfected with the vSAG-9 gene. Whereas some of the hybridomas recognized vSAG-9 exclusively in the context of H-2a, other hybridomas recognized vSAG-9 exclusively in the context of H-2d or in the context of both H-2d and H-2a. These results suggest that: (a) the class II MHC molecule plays a direct role in the recognition of retroviral superantigen by T cells, rather than serving simply as a platform for presentation; and, (b) it is likely that components of the TCR other than V beta are involved in the vSAG-9/TCR/class II interaction.

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Activation of Human Dendritic Cells Is Modulated by Components of the Outer Membranes of Neisseria meningitidis

Infection and Immunity ◽

10.1128/iai.71.10.5590-5597.2003 ◽

2003 ◽

Vol 71 (10) ◽

pp. 5590-5597 ◽

Cited By ~ 21

Author(s):

Tamara Al-Bader ◽

Myron Christodoulides ◽

John E. Heckels ◽

Judith Holloway ◽

Amanda E. Semper ◽

...

Keyword(s):

T Cells ◽

Dendritic Cells ◽

Neisseria Meningitidis ◽

Mrna Expression ◽

Mhc Class Ii ◽

Human Monocyte ◽

Class Ii ◽

Effective Vaccine ◽

Tlr4 Mrna ◽

Mhc Class Ii Molecules

ABSTRACT Neisseria meningitidis serogroup B is a major cause of life-threatening meningitis and septicemia worldwide, and no effective vaccine is available. Initiation of innate and acquired immune responses to N. meningitidis is likely to be dependent on cellular responses of dendritic cells (DC) to antigens present in the outer membrane (OM) of the meningococcus. In this study, the responses of human monocyte-derived DC (mo-DC) to OM isolated from parent (lipopolysaccharide [LPS]-replete) meningococci and from a mutant deficient in LPS were investigated. Parent OM selectively up-regulated Toll-like receptor 4 (TLR4) mRNA expression and induced mo-DC maturation, as reflected by increased production of chemokines, proinflammatory cytokines, and CD83, CD80, CD86, CD40, and major histocompatibility complex (MHC) class II molecules. In contrast, LPS-deficient OM selectively up-regulated TLR2 mRNA expression and induced moderate increases in both cytokine production and expression of CD86 and MHC class II molecules. Preexposure to OM, with or without LPS, augmented the allostimulatory properties of mo-DC, which induced proliferation of naive CD4+ CD45RA+ T cells. In addition, LPS-replete OM induced a greater gamma interferon/interleukin-13 ratio in naive T cells, whereas LPS-deficient OM induced the reverse profile. These data demonstrate that components of the OM, other than LPS, are also likely to be involved in determining the levels of DC activation and the nature of the T-helper immune response.

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In Vivo Evidence for the Contribution of Human Histocompatibility Leukocyte Antigen (Hla)-Dq Molecules to the Development of Diabetes

Journal of Experimental Medicine ◽

10.1084/jem.191.1.97 ◽

2000 ◽

Vol 191 (1) ◽

pp. 97-104 ◽

Cited By ~ 74

Author(s):

Li Wen ◽

F. Susan Wong ◽

Jie Tang ◽

Ning-Yuan Chen ◽

Martha Altieri ◽

...

Keyword(s):

T Cells ◽

Transgenic Mice ◽

Mhc Class Ii ◽

Spontaneous Diabetes ◽

Class Ii ◽

Β Cells ◽

Leukocyte Antigen ◽

Hla Dqa1 ◽

Mhc Class Ii Molecules

Although DQA1*0301/DQB1*0302 is the human histocompatibility leukocyte antigen (HLA) class II gene most commonly associated with human type 1 diabetes, direct in vivo experimental evidence for its diabetogenic role is lacking. Therefore, we generated C57BL/6 transgenic mice that bear this molecule and do not express mouse major histocompatibility complex (MHC) class II molecules (DQ8+/mII−). They did not develop insulitis or spontaneous diabetes. However, when DQ8+/mII− mice were bred with C57BL/6 mice expressing costimulatory molecule B7-1 on β cells (which normally do not develop diabetes), 81% of the DQ8+/mII−/B7-1+ mice developed spontaneous diabetes. The diabetes was accompanied by severe insulitis composed of both T cells (CD4+ and CD8+) and B cells. T cells from the diabetic mice secreted large amounts of interferon γ, but not interleukin 4, in response to DQ8+ islets and the putative islet autoantigens, insulin and glutamic acid decarboxylase (GAD). Diabetes could also be adoptively transferred to irradiated nondiabetic DQ8+/mII−/B7-1+ mice. In striking contrast, none of the transgenic mice in which the diabetes protective allele (DQA1*0103/DQB1*0601, DQ6 for short) was substituted for mouse MHC class II molecules but remained for the expression of B7-1 on pancreatic β cells (DQ6+/mII−/B7-1+) developed diabetes. Only 7% of DQ−/mII−/B7-1+ mice developed diabetes at an older age, and none of the DQ−/mII+/B7-1+ mice or DQ8+/mII+/B7-1+ mice developed diabetes. In conclusion, substitution of HLA-DQA1*0301/DQB1*0302, but not HLA-DQA1*0103/DQB1*0601, for murine MHC class II provokes autoimmune diabetes in non–diabetes-prone rat insulin promoter (RIP).B7-1 C57BL/6 mice. Our data provide direct in vivo evidence for the diabetogenic effect of this human MHC class II molecule and a unique “humanized” animal model of spontaneous diabetes.

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The importance of the back–signal from T cells into antigen–presenting cells in determining susceptibility to parasites

Philosophical Transactions of the Royal Society B Biological Sciences ◽

10.1098/rstb.1997.0117 ◽

1997 ◽

Vol 352 (1359) ◽

pp. 1327-1330 ◽

Cited By ~ 7

Author(s):

Brigitte Müller ◽

Avrion Mitchison

Keyword(s):

T Cells ◽

Immune Responses ◽

Mhc Class Ii ◽

Class Ii ◽

Activated T Cells ◽

Ifn Gamma ◽

Parasite Infections ◽

Antigen Presenting ◽

Mhc Class Ii Genes ◽

Mhc Class Ii Molecules

It has long been known that certain MHC class II genes can dominantly suppress immune responses and so increase susceptibility to parasite infections, but the mechanism has been unclear. Recent work has revealed one way in which this form of suppression may operate through gating by MHC class II molecules of the back–signal from activated T cells into macrophages. The two known suppressive genes of the mouse are expressed in macrophages more extensively than are other class II genes. This is asscociated with suppresion of IL–4 production resulting, we infer, from overproduction in the macrophages of IL–12, the counter–cytokine to IL–4. The lack of IL–4 may itself be immunosuppressive, even for Th2 responses, and excess IL–12 can overinduce the antiproliferative cytokine IFN–gamma. Although this mechanism requires further substantiation, we believe that it offers a reasonable answer to an old conundrum.

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Major Histocompatibility Complex Class II-Independent Generation of Neutralizing Antibodies against T-Cell-Dependent Borrelia burgdorferi Antigens Presented by Dendritic Cells: Regulation by NK and γδ T Cells

Infection and Immunity ◽

10.1128/iai.69.4.2407-2415.2001 ◽

2001 ◽

Vol 69 (4) ◽

pp. 2407-2415 ◽

Cited By ~ 11

Author(s):

M. Lamine Mbow ◽

Nordin Zeidner ◽

Robert D. Gilmore ◽

Marc Dolan ◽

Joseph Piesman ◽

...

Keyword(s):

T Cells ◽

Dendritic Cells ◽

Major Histocompatibility Complex ◽

Borrelia Burgdorferi ◽

Mhc Class Ii ◽

Γδ T Cells ◽

Humoral Response ◽

Class Ii ◽

Histocompatibility Complex ◽

Mhc Class Ii Molecules

ABSTRACT We previously showed that adoptive transfer of Borrelia burgdorferi-pulsed dendritic cells (DCs) into syngeneic mice protects animals from challenge with tick-transmitted spirochetes. Here, we demonstrate that the protective immune response is antibody (Ab) dependent and does not require the presence of major histocompatibility complex (MHC) class II molecules on DCs. Mice sensitized with B. burgdorferi-pulsed MHC class II-deficient (MHC class II−/−) DCs mounted a humoral response against protective antigens, includingB. burgdorferi outer surface protein A (OspA) and OspC. B-cell help for the generation of neutralizing anti-OspC immunoglobulin G Abs could be provided by γδ T cells. In contrast, anti-OspA Ab production required the presence of αβ T cells, although this pathway could be independent of MHC class II molecules on antigen-presenting cells. Moreover, depletion of NK cells prior to transfer of antigen-pulsed MHC class II−/− DCs resulted in significant increases in the levels of neutralizing Abs induced by DCs. Altogether, these data suggest that the initial interactions between DCs and innate immune cells, such as γδ and NK cells, can influence the generation of a protective humoral response againstB. burgdorferi antigens.

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Peripheral Pool of CD8+T-Cells Contains Lymphocytes with Antigen-Specific Receptors That Recognize Syngeneic MHC Class II Molecules

Russian Journal of Developmental Biology ◽

10.1023/b:rudo.0000029712.45718.65 ◽

2004 ◽

Vol 35 (3) ◽

pp. 142-147

Author(s):

L. A. Pobezinsky ◽

E. L. Pobezinskaya ◽

T. S. Grinenko ◽

A. V. Chervonskii ◽

D. B. Kazansky

Keyword(s):

T Cells ◽

Mhc Class Ii ◽

Cd8 T Cells ◽

Class Ii ◽

Specific Receptors ◽

Mhc Class Ii Molecules

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PEPTIDES FROM TOLEROGENIC MHC CLASS II MOLECULES ACTIVATE REGULATORY T CELLS.

Transplantation Journal ◽

10.1097/00007890-200607152-02913 ◽

2006 ◽

Vol 82 (Suppl 2) ◽

pp. 1024

Author(s):

&NA;

Keyword(s):

T Cells ◽

Regulatory T Cells ◽

Mhc Class Ii ◽

Class Ii ◽

Mhc Class Ii Molecules

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Humanized E17 Hemophilic Mice Are a Major Breakthrough in the Design of New Preclinical Models for Developing Factor VIII Products with Reduced Immunogenicity.

Blood ◽

10.1182/blood.v110.11.782.782 ◽

2007 ◽

Vol 110 (11) ◽

pp. 782-782 ◽

Cited By ~ 1

Author(s):

Birgit M. Reipert ◽

Christina Hausl ◽

Maria Sasgary ◽

Maria Schuster ◽

Rafi U. Ahmad ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Immune Responses ◽

Factor Viii ◽

Mhc Class Ii ◽

Cd4 T Cells ◽

Plasma Cells ◽

Hemophilia A ◽

Class Ii ◽

Mhc Class Ii Molecules

Abstract MHC class II molecules are crucial for regulating adaptive immune responses against self and foreign protein antigens. They determine the antigenic peptides that are presented to CD4+ T cells and are essential for shaping the CD4+ T-cell repertoire in the thymus. Thus, the structure of MHC class II molecules is a major determinant for protein antigen immunogenicity. Structural differences between murine and human MHC class II complexes fundamentally limit the use of conventional murine hemophilia A models for dissecting immune responses to human factor VIII and developing new factor VIII products with reduced immunogenicity. To overcome this limitation, we humanized the murine E17 model of hemophilia A by introducing the human MHC class II haplotype HLA-DRB1*1501 on the background of a complete knockout of all murine MHC class II genes. Any anti-FVIII antibody response in this new humanized hemophilia A model is driven by CD4+ T cells that recognize FVIII-derived peptides that are presented by human HLA-DRB1*1501. The MHC class II haplotype HLA-DRB1*1501 is particularly relevant for the situation in hemophilia A patients because it is found in about 25% of Caucasians and 32% of Africans and has been shown to be associated with an increased risk that patients with severe hemophilia A have for developing FVIII inhibitors. We validated the relevance of this new model by asking the question whether HLA-DRB1*1501 hemophilic E17 mice develop FVIII inhibitors that are similar to those observed in patients with hemophilia A. Furthermore, we wanted to show that anti-FVIII antibody responses in these mice depend on the expression of the human DRB1*1501 molecule. Mice were treated with 8 intravenous doses of human FVIII and tested for anti-FVIII antibodies, anti-FVIII antibody-producing plasma cells and FVIII-specific T cells. About 90% of all humanized hemophilic E17 mice tested developed anti-FVIII antibodies that were similar to FVIII inhibitors found in patients. These antibodies were not restricted isotypically and contained mainly IgG1, IgG2a and IgG2b antibodies. Detection of antibodies in the circulation correlated with the presence of anti-FVIII antibody-producing plasma cells in the spleen. Development of anti-FVIII antibodies depended on the activation of FVIII-specific T cells and strictly depended on the expression of the HLA-DRB1*1501 molecule. Mice that did not express any MHC class II molecules did not develop anti-FVIII antibodies. We conclude that this new humanized E17 model for hemophilia A is a major advance towards developing suitable animal models needed to design future immunomodulatory strategies for patients with FVIII inhibitors and develop new FVIII products with reduced immunogenicity. Furthermore, it provides a tool for identifying T-cell epitopes of human FVIII restricted by MHC class II molecules that can be used for monitoring FVIII-specific T cells in patients who receive replacement therapy with FVIII products.

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