T-cells specifically recognize their target antigens because they have antigen receptors on their surfaces. Two antigen receptors have been defined. Each of these receptors is though to consist of two immunoglobulin-like polypeptides (alpha and beta or delta and gamma) and they are designated the alpha-beta and delta- gamma receptors respectively. A central concept in our understanding of the interaction between normal T-cells and their target antigens is that the alpha-beta receptor recognizes a foreign antigen in the context of a polymorphic MHC antigen. However, T-cells bearing the delta-gamma receptor appear to be able to recognize target cells in an MHC non-restricted fashion. That is, the delta-gamma receptor does not appear to recognized it antigen in the context of a particular MHC molecule. Eventually we would like to understand how these receptors react with antigens. Furthermore, the delta chain gene rearranges early during the development of a particular T-cell. We propose that expression of a functional delta-gamma chain prevents further T-cell maturation. We propose here to characterize the genes encoding the delta chain and to reconstitute both alpha-beta and delta-gamma receptors in both transformed T-cells and transgenic mice and to use these new reagents to address these issues. Specifically we propose to: 1) clone a cDNA encoding the delta chain of the delta-gamma receptor. 2) Characterize the genes encoding this chain. 3) Clone and express genes encoding alpha and beta chains from receptors with known function. 4) Make transgenic mice that express the clone delta, alpha, and beta chain genes. 5) Determine the effect of the expressed transgene on the development of the T-cell repertoire in these mice. 6) To make transgenic mice that express functional T-cell receptors and to examine the effect of these receptors on the development of the T-cell repertoire.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI019148-10
Application #
3128551
Study Section
Allergy and Immunology Study Section (ALY)
Project Start
1982-07-01
Project End
1992-06-30
Budget Start
1991-07-01
Budget End
1992-06-30
Support Year
10
Fiscal Year
1991
Total Cost
Indirect Cost
Name
Harvard University
Department
Type
Schools of Medicine
DUNS #
082359691
City
Boston
State
MA
Country
United States
Zip Code
02115
Barrett, L V; Rimm, I J; Wiens, G R et al. (1991) Allorecognition in T-cell receptor (beta-chain) transgenic mice. Surgery 110:385-8;discussion 388-9
Holcombe, R F; van de Griend, R; Ang, S L et al. (1990) Gamma-delta T cells in Chediak-Higashi syndrome. Acta Haematol 83:193-7
Fox, V L; Strauss, W M; Seidman, J G (1989) Isolation and restriction map of the V-J interval of the human T cell receptor gamma chain locus. Genomics 4:445-8
Kim, S Y; Ang, S L; Bloch, D B et al. (1988) Identification of cDNA encoding an additional alpha subunit of a human GTP-binding protein: expression of three alpha i subtypes in human tissues and cell lines. Proc Natl Acad Sci U S A 85:4153-7
Neer, E J; Kim, S Y; Ang, S L et al. (1988) Functions of G-protein subunits. Cold Spring Harb Symp Quant Biol 53 Pt 1:241-6
Van Dongen, J J; Wolvers-Tettero, I L; Seidman, J G et al. (1987) Two types of gamma T cell receptors expressed by T cell acute lymphoblastic leukemias. Eur J Immunol 17:1719-28
Ang, S L; Seidman, J G; Peterman, G M et al. (1987) Functional gamma chain-associated T cell receptors on cerebrospinal fluid-derived natural killer-like T cell clones. J Exp Med 165:1453-8
Borst, J; van de Griend, R J; van Oostveen, J W et al. (1987) A T-cell receptor gamma/CD3 complex found on cloned functional lymphocytes. Nature 325:683-8
Holcombe, R F; Strauss, W; Owen, F L et al. (1987) Relationship of the genes for Chediak-Higashi syndrome (beige) and the T-cell receptor gamma chain in mouse and man. Genomics 1:287-91
Parker, K L; Schimmer, B P; Chaplin, D D et al. (1986) Characterization of a regulatory region of the steroid 21-hydroxylase gene. J Biol Chem 261:15353-5

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