Activation of murine T cells by staphylococcal enterotoxin E: Requirement of MHC class II molecules expressed on accessory cells and identification of Vβ sequence of T cell receptors in T cells reactive to the toxin

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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The toxicity of staphylococcal enterotoxin B in mice is mediated by T cells.

Journal of Experimental Medicine ◽

10.1084/jem.171.2.455 ◽

1990 ◽

Vol 171 (2) ◽

pp. 455-464 ◽

Cited By ~ 210

Author(s):

P Marrack ◽

M Blackman ◽

E Kushnir ◽

J Kappler

Keyword(s):

Weight Loss ◽

T Cells ◽

T Cell ◽

Mhc Class Ii ◽

Cell Function ◽

Class Ii ◽

Staphylococcal Enterotoxin ◽

Staphylococcal Enterotoxin B ◽

Rapid Weight Loss ◽

Enterotoxin B

Staphylococcal enterotoxin B (SEB) has been shown in the past to be a potent T cell stimulant in mouse or man. The toxin acts as a superantigen that is, it binds to class II MHC proteins and, as such a complex, stimulates T cells bearing particular V beta s as part of their receptors. The toxin also has several pathological effects, causing, in mice, rapid weight loss, thymus atrophy, immunosuppression, and, at high doses, death. The data in this paper show that at least one of these effects, weight loss, is T cell mediated. Staphylococcal enterotoxin-mediated weight loss is MHC dependent, and is almost absent in animals expressing MHC class II molecules, which, complexed with SEB, are poor T cell stimulants. Also, mice that lack T cell function, genetically or because of cyclosporin A treatment, lose no or less weight than controls in response to SEB. Finally, animals bred such that they express few T cells bearing V beta s with which SEB can interact lose much less weight in response to the toxin than littermate controls that have higher numbers of reactive T cells. It is therefore suggested that the pathological effects of the staphylococcal, T cell-stimulating toxins in mouse and man may be partially or wholly the consequence of massive T cell stimulation.

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Antigen presentation by mouse CD4+ T cells involving acquired MHC class II:peptide complexes: another mechanism to limit clonal expansion?

Blood ◽

10.1182/blood-2002-04-1230 ◽

2003 ◽

Vol 101 (7) ◽

pp. 2704-2710 ◽

Cited By ~ 72

Author(s):

Julia Y. S. Tsang ◽

Jian Guo Chai ◽

Robert Lechler

Keyword(s):

T Cells ◽

T Cell ◽

Antigen Presentation ◽

Mhc Class Ii ◽

Cd4 T Cells ◽

Interleukin 2 ◽

Clonal Expansion ◽

Class Ii ◽

Hybridoma Cells ◽

Mhc Class Ii Molecules

Antigen presentation by activated human and rat CD4+ T cells has long been known to induce hyporesponsiveness due to a combination of anergy and apoptosis. It has been assumed that no such phenomenon occurs in mice due to the inability of mouse T cells to synthesize major histocompatibility complex (MHC) class II molecules. There have been several recent descriptions of the transfer of molecules, including MHC molecules, from antigen-presenting cells (APCs) to T cells. Here, we describe the acquisition of MHC class II molecules by T-cell receptor (TCR)–transgenic T cells and T-hybridoma cells following culture with APCs. Acquisition was markedly enhanced by T-cell activation either due to cognate recognition of antigen or anti-CD3 activation. When activation was induced by antigen recognition, preferential acquisition of complexes of class II molecules displaying cognate peptide was observed; in contrast, following activation by anti-CD3 the acquisition of class II molecules was MHC unrestricted. T cells that had acquired MHC class II:peptide complexes were able to act as APCs and induced proliferation and interleukin-2 secretion by resting T cells. However, when activated T cells that had acquired MHC class II:peptide complexes engaged in T:T interactions, this led to an increase in apoptosis and the induction of hyporesponsiveness. These results raise the possibility that the acquisition of MHC class II:peptide complexes by T cells during an immune response may serve to limit clonal expansion, including that induced by alloantigen following tissue or stem cell transplantation.

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Major histocompatibility complex independent clonal T cell anergy by direct interaction of Staphylococcus aureus enterotoxin B with the T cell antigen receptor.

Journal of Experimental Medicine ◽

10.1084/jem.175.6.1493 ◽

1992 ◽

Vol 175 (6) ◽

pp. 1493-1499 ◽

Cited By ~ 92

Author(s):

C R Hewitt ◽

J R Lamb ◽

J Hayball ◽

M Hill ◽

M J Owen ◽

...

Keyword(s):

Staphylococcus Aureus ◽

T Cells ◽

Major Histocompatibility Complex ◽

T Cell ◽

Mhc Class Ii ◽

Direct Interaction ◽

Class Ii ◽

Cell Antigen ◽

Histocompatibility Complex ◽

Mhc Class Ii Molecules

The Staphylococcal enterotoxin superantigens stimulate vigorous responses in T cells bearing certain T cell antigen receptor (TCR) V beta regions. In addition to activation, these superantigens also impart negative signals to T cells resulting in a profound state of unresponsiveness or anergy. The Staphylococcus aureus enterotoxins (SE) B and C2 bind to a closely related site on major histocompatibility complex (MHC) human leukocyte antigen (HLA)-DR1 molecules. Only SEB, however, interacts with the TCR V beta 3 region of HA1.7, a human HLA-DR1 restricted T cell clone specific for influenza haemagglutinin. In competition experiments, we demonstrated that the induction of anergy in HA1.7 by SEB is unaffected by the presence of SEC2. These results suggest that SEB-induced anergy is MHC independent and involves a direct interaction between the TCR and SEB. To resolve definitively whether SEB binds directly to T cells in the absence of MHC class II molecules, the cDNAs encoding the HA1.7 TCR were transfected into an MHC class II-negative human T cell line. The addition of SEB to these transfectants resulted in the downregulation of cell surface TCR expression, an increase in the concentration of intracellular calcium ions, the production of lymphokines, and reduced responsiveness to a subsequent challenge with SEB. We conclude that SEB interacts directly with the TCR in the absence of cointeraction with MHC class II molecules, and that this interaction may induce anergy in HA1.7.

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Interactions of CD4 with MHC class II molecules, T cell receptors and p56 lck

Philosophical Transactions of the Royal Society B Biological Sciences ◽

10.1098/rstb.1993.0130 ◽

1993 ◽

Vol 342 (1299) ◽

pp. 13-24 ◽

Cited By ~ 9

Keyword(s):

T Cell ◽

Mhc Class Ii ◽

T Cell Receptors ◽

Protein Tyrosine Kinase ◽

Cell Receptor ◽

Class Ii ◽

Cell Receptors ◽

Multimeric Complex ◽

And Function ◽

Immunoglobulin Supergene Family

CD4 and CD8 are members of the immunoglobulin supergene family of proteins, and function as co-receptors with the T cell receptor (TCR) in binding MHC class II or class I molecules, respectively. Within this multimeric complex, CD4 interacts with three distinct ligands. CD4 interacts through its D1 and D2 domains with MHC class II proteins, through its D3 and D4 domains with T cell receptors, and through its cytoplasmic tail with p56 lck , a src -related, protein tyrosine kinase. Each of these interactions is important in the function of CD4 and will be discussed in turn.

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T cell proliferation induced by anti-self-I-A-specific T cell hybridomas. Evidence of a T cell network.

Journal of Experimental Medicine ◽

10.1084/jem.164.2.490 ◽

1986 ◽

Vol 164 (2) ◽

pp. 490-500 ◽

Cited By ~ 12

Author(s):

D W Kennedy ◽

C Russo ◽

Y T Kim ◽

M E Weksler

Keyword(s):

Cell Proliferation ◽

T Cells ◽

T Cell ◽

Mhc Class Ii ◽

T Cell Receptors ◽

T Cell Proliferation ◽

Cell Receptors ◽

Cell Network ◽

Recombinant Mice ◽

Stimulation Of

Allo-I-A-reactive T cell hybridomas were generated from MLR-activated lymphoblasts. Cloned hybridomas T1.203, T1.321, and T1.426 were stimulated by I-Ab determinants, as shown by their ability to secrete IL-2 in response to a panel of MHC-recombinant mice. T2.146, T2.205, and T3.116 were found to be specific for I-Ak determinants using a similar panel of MHC-recombinant mice. Inhibition of IL-2 secretion by anti-I-A mAb confirmed these data. Some I-Ab-specific hybrids stimulated the proliferation of T cells from C57BL/6 (H-2b) mice. Similarly, some I-Ak-specific hybrids stimulated the proliferation of T cells from C3H/HeJ (H-2k) mice. These hybrids expressed no detectable surface I-A, and stimulation of T cells was not inhibited by anti-I-A mAb. These results are consistent with the hypothesis that normal mice possess a population of T cells responsive to idiotypic determinants on anti-MHC class II T cell receptors.

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