Our long term objective is to understand the basis of the selection of the T cell receptor during thymocyte ontogeny. Mature, peripheral helper and killer T cells recognize foreign antigens as peptides fragments presented in a groove on the major histocompatibility complex encoded class II and class I molecules respectively. The T cell receptor contact sites on the peptide and on the self presenting molecule. The histocompatibility loci are extremely polymorphic. The various alleles bind different peptides and have different T cell receptor contacts. To ensure T cell recognition of foreign peptide is as efficient as possible, the thymic (self) histocompatibility molecules select which clones for immature T cells survive and populate the periphery. We propose to study this process of thymus selection using a range of closely related mutant self molecules (Kb mutants) and peptide antigens derived from ovalbumin and other class I Kb-restricted antigens such as Vesicular Stomatitis virus nucleocapsid protein. Knowledge gained in this area could have an immediate impact on the design of bone-marrow transplantation therapies. The information is also part of our understanding the T cell response to any infectious agent and in autoimmune diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI029802-04
Application #
3144701
Study Section
Allergy & Clinical Immunology-1 (AITC)
Project Start
1989-09-15
Project End
1994-07-31
Budget Start
1992-08-01
Budget End
1993-07-31
Support Year
4
Fiscal Year
1992
Total Cost
Indirect Cost
Name
University of Washington
Department
Type
Schools of Medicine
DUNS #
135646524
City
Seattle
State
WA
Country
United States
Zip Code
98195
Lehar, Sophie M; Bevan, Michael J (2006) T cells develop normally in the absence of both Deltex1 and Deltex2. Mol Cell Biol 26:7358-71
Lehar, Sophie M; Dooley, James; Farr, Andrew G et al. (2005) Notch ligands Delta 1 and Jagged1 transmit distinct signals to T-cell precursors. Blood 105:1440-7
Yun, Theodore J; Bevan, Michael J (2003) Notch-regulated ankyrin-repeat protein inhibits Notch1 signaling: multiple Notch1 signaling pathways involved in T cell development. J Immunol 170:5834-41
Huang, Eugene Y; Gallegos, Alena M; Richards, Sabrina M et al. (2003) Surface expression of Notch1 on thymocytes: correlation with the double-negative to double-positive transition. J Immunol 171:2296-304
Krebs, L T; Deftos, M L; Bevan, M J et al. (2001) The Nrarp gene encodes an ankyrin-repeat protein that is transcriptionally regulated by the notch signaling pathway. Dev Biol 238:110-9
Goldrath, A W; Bogatzki, L Y; Bevan, M J (2000) Naive T cells transiently acquire a memory-like phenotype during homeostasis-driven proliferation. J Exp Med 192:557-64
Deftos, M L; Huang, E; Ojala, E W et al. (2000) Notch1 signaling promotes the maturation of CD4 and CD8 SP thymocytes. Immunity 13:73-84
Kirchner, J; Bevan, M J (1999) ITM2A is induced during thymocyte selection and T cell activation and causes downregulation of CD8 when overexpressed in CD4(+)CD8(+) double positive thymocytes. J Exp Med 190:217-28
Goldrath, A W; Bevan, M J (1999) Low-affinity ligands for the TCR drive proliferation of mature CD8+ T cells in lymphopenic hosts. Immunity 11:183-90
Deftos, M L; He, Y W; Ojala, E W et al. (1998) Correlating notch signaling with thymocyte maturation. Immunity 9:777-86

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