The immune response to most antigens requires activation of CD4-T cells. These T-cells are activated by recognizing antigen in the form of peptide fragments bound to class II MHC molecules on the surface of another cell. Although the structure of the T-cell receptor (TCR) on such cells is well characterized, little is known of the actual nature of this receptor:ligand interaction. In particular, the orientation of the TCR to MHC molecules, the role of the CD4 co-receptor molecule, the role of Mls locus products and related proteins, and the binding of natural peptides to MHC molecules is uncertain. The applicants' working hypothesis is that the TCR:class II MHC interaction is precisely oriented, and that this orientation is determined, at least in part, by the binding of the co-receptor molecule both to the ligand and to the TCR. The complex is further oriented by binding of the Mls locus product and related proteins to the same two structures during antigen recognition; the applicants propose the term """"""""co-ligand"""""""" for these latter structures. The applicants will use a unique cellular system developed in their laboratory along with molecular and cell biological techniques to characterize this receptor:ligand interaction in greater detail. This project has four specific questions it seeks to answer. 1. What is the nature of contacts between TCR molecules and their MHC ligands? The applicants' studies suggest that V gene segment encoded portions of the TCR may preferentially interact with the MHC molecule. The applicants will use monoclonal antibodies, receptor transfection, and mutagenesis to test this point, taking advantage of the unique cellular system they have devised. 2. What is the nature of CD4:TCR interaction? The applicants will use murine T-cells transfected with human CD4, and with chimeric genes encoding portions of both human and mouse CD4, to assess this molecular interaction. The applicants will examine the phosphorylation of the TCR induced by CD4 cross-linking. The applicants also seek to determine whether CD4 and CD8 lead to the same effects, or whether there is evidence for distinctive signals transduced by such receptors. 3. What is the nature of the Mls locus product, and how does it produce its effects? The applicants will use the staphylococcal enterotoxins to examine this question, including soluble and transfected forms of this protein. The applicants plan to make transgenic mice expressing this Mls analogue in various tissues. Finally, the applicants will attempt to raise antibodies to the Mls locus products, using a novel approach they have devised. 4. What is the nature of the TCR ligand generated in vivo? The applicants have prepared a monoclonal antibody to what appears to be a self-peptide presented by class II MHC. The applicants will attempt to produce further antibodies of this specificity. The applicants will also analyze the antibody they have to determine the exact nature of its ligand, the process by which this ligand is generated, and the molecular details of the interaction of the antibody with its ligand.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Method to Extend Research in Time (MERIT) Award (R37)
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Immunological Sciences Study Section (IMS)
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Yale University
Schools of Medicine
New Haven
United States
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Viret, Christophe; He, Xin; Janeway Jr, Charles A (2003) Altered positive selection due to corecognition of floppy peptide/MHC II conformers supports an integrative model of thymic selection. Proc Natl Acad Sci U S A 100:5354-9
Viret, Christophe; Janeway Jr, Charles A (2003) Self-specific MHC class II-restricted CD4-CD8- T cells that escape deletion and lack regulatory activity. J Immunol 170:201-9
Bynoe, Margaret S; Evans, J Tori; Viret, Christophe et al. (2003) Epicutaneous immunization with autoantigenic peptides induces T suppressor cells that prevent experimental allergic encephalomyelitis. Immunity 19:317-28
He, Xin; Janeway Jr, Charles A; Levine, Matthew et al. (2002) Dual receptor T cells extend the immune repertoire for foreign antigens. Nat Immunol 3:127-34
Viret, C; Sant'Angelo, D B; He, X et al. (2001) A role for accessibility to self-peptide-self-MHC complexes in intrathymic negative selection. J Immunol 166:4429-37
Das, G; Sheridan, S; Janeway Jr, C A (2001) The source of early IFN-gamma that plays a role in Th1 priming. J Immunol 167:2004-10
Viret, C; He, X; Janeway Jr, C A (2001) Paradoxical intrathymic positive selection in mice with only a covalently presented agonist peptide. Proc Natl Acad Sci U S A 98:9243-8
Viret, C; Janeway Jr, C A (2000) Functional and phenotypic evidence for presentation of E alpha 52-68 structurally related self-peptide(s) in I-E alpha-deficient mice. J Immunol 164:4627-34
Viret, C; Lantz, O; He, X et al. (2000) A NK1.1+ thymocyte-derived TCR beta-chain transgene promotes positive selection of thymic NK1.1+ alpha beta T cells. J Immunol 165:3004-14
Medzhitov, R; Janeway Jr, C A (2000) How does the immune system distinguish self from nonself? Semin Immunol 12:185-8; discussion 257-344

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