The vertebrate immune responses to infectious agents are regulated and mediated by T lymphocytes. The primary event in this immune induction is a recognition of foreign antigenic determinants by a receptor present in the plasma membrane of the T cell.
The aims of this proposal focus on the molecular properties of the T cell antigen receptor, and hence of the basis of antigen-specific immunity. In order to investigate the structure of the T cell receptor, a recombinant DNA clone we recently isolated will be used to isolate cDNA clones from T cell hybridomas of defined specificity for antigen and major histocompatibility complex (MHC) molecules. A comparison of the sequence of the receptor genes from these cell lines will be carried out in order to understand how the receptor simultaneously distinguishes differences in both antigen and MHC determinants.
A second aim of this proposal is to investigate the maturation of T cells with respect to the ontogeny of receptor expression, focusing on the stage at which receptor expression first occurs, and on the levels of receptor expression at the different stages of T cell maturation. The importance of these experiments relates to mechanisms of T cell selection for self and nonself recognition. Further experiments proposed are designed to facilitate the isolation of antibodies specific for the constant region of the T cell receptor. These experiments will take advantage of a procaryotic expression vector to produce an immunogenic polypeptide containing the entire constant region of the receptor. Using recombinant DNA techniques the experiments described in this proposal will address several of the fundamental questions concerning T cell biology, questions not previously approachable prior to the molecular cloning of T cell receptor genes.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Modified Research Career Development Award (K04)
Project #
5K04AI000662-04
Application #
3070741
Study Section
Allergy and Immunology Study Section (ALY)
Project Start
1985-07-01
Project End
1990-06-30
Budget Start
1988-07-01
Budget End
1989-06-30
Support Year
4
Fiscal Year
1988
Total Cost
Indirect Cost
Name
University of California Los Angeles
Department
Type
Schools of Arts and Sciences
DUNS #
119132785
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
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Vasquez, N J; Kaye, J; Hedrick, S M (1992) In vivo and in vitro clonal deletion of double-positive thymocytes. J Exp Med 175:1307-16
Bhayani, H R; Hedrick, S M (1991) The role of polymorphic amino acids of the MHC molecule in the selection of the T cell repertoire. J Immunol 146:1093-8
Kawasaki, H; Becker, M L; Hedrick, S M (1991) Specificity for molecules of the major histocompatibility complex mediated by a hybrid immunoglobulin-T cell receptor. New Biol 3:487-97
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Dent, A L; Fink, P J; Hedrick, S M (1989) Characterization of an alternative exon of the murine T cell receptor beta-chain. Pattern of expression and evolutionary conservation. J Immunol 143:322-8
Becker, M L; Near, R; Mudgett-Hunter, M et al. (1989) Expression of a hybrid immunoglobulin-T cell receptor protein in transgenic mice. Cell 58:911-21
Engel, I; Hedrick, S M (1988) Site-directed mutations in the VDJ junctional region of a T cell receptor beta chain cause changes in antigenic peptide recognition. Cell 54:473-84
Hedrick, S M (1988) Specificity of the T cell receptor for antigen. Adv Immunol 43:193-234
Hedrick, S M; Engel, I; McElligott, D L et al. (1988) Selection of amino acid sequences in the beta chain of the T cell antigen receptor. Science 239:1541-4

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