Recent data suggest that the adaptive immune system is basically self-referential. This is well established for T cells, which recognize antigen only when it is presented by the MHC molecules that these T cells have been selected upon. It is far less clear what role self-recognition plays in the onward survival of T cells or in their activation. Even more obscure is the positive selection of mature B cells we have recently reported. We propose to explore these issues in four specific aims in this grant. These are as follows: 1. What is the role of self- peptide: self-MHC complexes in the development of the mature T cell receptor repertoire in the thymus? Do the same rules apply for MHC class I molecules as were previously observed with MHC class II molecules? We hypothesize that self-recognition applies to all MHC class II-restricted TCRs, and we will confirm this by testing several examples, as well as 3 MHC class I-restricted TCRs to see if MHC class I restricted TCRs obey the same rules. 2. What is the role of self-peptide: self-MHC complexes in the periphery in maintaining the mature, peripheral T cell receptor repertoire? We hypothesize that this interaction sustains T cells in the periphery, and that this process is accompanied by slow turn-over of mature T cells. 3. Does self-peptide: self-MHC recognition contribute to antigen stimulation? We hypothesize that the ability of small numbers of foreign peptides to trigger T cells is due to their ability to cause tight adhesion between a T cell and an antigen-presenting cell, leading to effective engagement of the T cell receptor with self-peptide: self-MHC complexes. 4. What is responsible for the positive selection of B cells, and for the stable maintenance of mature B cells in the periphery? We hypothesize that it is self-antigen recognition at a sub-threshold level, leading to a highly restricted set of B cell receptors. We will test these hypotheses in a variety of ways to determine their correctness.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI014579-23
Application #
6349769
Study Section
Immunobiology Study Section (IMB)
Program Officer
Nabavi, Nasrin N
Project Start
1978-02-01
Project End
2005-01-31
Budget Start
2001-02-01
Budget End
2002-01-31
Support Year
23
Fiscal Year
2001
Total Cost
$324,284
Indirect Cost
Name
Yale University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
082359691
City
New Haven
State
CT
Country
United States
Zip Code
06520
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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