The recognition of antigen by T cells is a seminal event in the induction of a specific immune response. The TCR recognizes a peptide bound to an MHC molecule (p/MHC) on the surface of an antigen presenting cell.! The TCR is a highly intricate receptor, but has a low affinity for the p/MHC ligand. The basis for thei exquisite TCR specificity, despite the low affinity, is still not known. A major advance in our understanding of how T cells recognize antigen has been the direct demonstration of the formation of an immunological synapse. The immunological synapse is a supramolecular structure at the interface between the T cell and a | single APC that is stable for many hours. The immunologicalsynapse provides the molecular machinery fori integration of p/MHC quality and quantity. These studies have provided a model explaining how a TCR can distinguish between closely related ligands, but many questions remain. In this proposal, our overall goal is to understand how mature T cells and thymocytes can respond to small kinetic and structural changes in the p/MHC ligands. Our laboratory has developed and utilized the Hb/I-Ek antigen system. We have generated and characterized a wide range of T cells, ligands, and transgenic mice for two T cells, 3.L2 and 2.102.i Through an integrated investigation of the 3.L2and 2.102 T cells and ligands we propose to explore several key issues including: 1) how do the TCR binding properties to a continuum of different strength ligands relate to their structure and biological effects, 2) how does the recognition by a single TCR of syngeneic and' allogeneic ligands compare, 3) how do immunological synapses in thymocytes compare to those of mature T cells, and 4) what is the role of CD4 in immunological synapse formation and TCR:p/MHC interactions? These proposed studies will provide key molecular details of the interaction between a TCR and the p/MHC ligand. These studies could lead to the development of novel pharmaceuticals which could control unwanted immune responses, such as an autoimmune response.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37AI024157-21
Application #
7371064
Study Section
Special Emphasis Panel (NSS)
Program Officer
Rothermel, Annette L
Project Start
1987-04-01
Project End
2012-02-29
Budget Start
2008-03-01
Budget End
2009-02-28
Support Year
21
Fiscal Year
2008
Total Cost
$335,502
Indirect Cost
Name
Washington University
Department
Pathology
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
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