The purpose of the present studies is to identify cells bearing Ia antigens encoded in the I region of the murine major histocompatibility complex (MHC) which influence the development and function of self Ia recognizing Lyt-1+ helper T cells. We anticipate studying four such cells: Veto cells, which are involved in clonal deletion of autoreactive T cells; Thymic epithelial cells, which are involved in expansion of self Ia recognizing Ly1 T cell precursors; Antigen presenting cells, which are involved in antigen-specific expansion of self Ia recognizing T cells in the periphery; and B cells, which are activated to proliferate and to secrete antibody in the presence of Ly1 helper T cells. We will identify and determine the functional activity of these cells with cloned T cell lines of known self and non-self Ia recognition capabilities, with monoclonal anti-Ia antibodies, and with monoclonal antibodies to other differentiation antigens, such as surface Ig on B cells. We will also test the interactions of each Ia bearing cell type with pre-T cells, with thymocytes, and with mature peripheral T cells. The importance of Ia antigen density on the surface of each cell type will be analyzed using F1 hybrid mice that express Ia antigen alleles unequally, allowing us to manipulate the density of Ia on cell surfaces in a defined fashion. We will examine the induction of tolerance in mature Ly1 T cells and suppressor T cells activated by interaction with such cloned helper T cell lines. From this study, a clear understanding of self tolerance and of the selective activation of self Ia recognizing helper T cells should emerge. This, in turn, should clarify the mechanism of action of Immune response genes (Ir genes), which in many instances appear to reflect tolerance to self antigens in the context of self Ia glycoproteins. Information about Ia antigen functions in mice should give insight into the influence of HLA antigens on disease susceptibility in man.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
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Experimental Immunology Study Section (EI)
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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
Sant'Angelo, Derek B; Janeway Jr, Charles A (2002) Negative selection of thymocytes expressing the D10 TCR. Proc Natl Acad Sci U S A 99:6931-6
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; Barlow, A K; Janeway Jr, C A (2000) Polymorphism of the mouse T-cell receptor AV20S1 gene. Immunogenetics 51:392-4
Levine, M H; Haberman, A M; Sant'Angelo, D B et al. (2000) A B-cell receptor-specific selection step governs immature to mature B cell differentiation. Proc Natl Acad Sci U S A 97:2743-8

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