FUNCTIONAL T CELL RECEPTOR GAMMA DELTA CELLS & GENES

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Two T cell receptors (TCR) exist. The TCR alphabeta exists as a disulfide-linked heterodimer. The genes encoding the TCR alpha and beta chains display homology with immunoglobulin light chains and are composed of variable (V), diversity (D), joining (J) and constant (C) regions which undergo rearrangements during T cell ontogeny. TCR alpha beta lymphocyte antigen recognition is known to be restricted by major histocompatibility (MHC) antigens, but the nature of the interaction between receptor gene segment usage, MHC restriction, and/or antigen recognition remains unclear. A second T cell receptor heterodimer on peripheral blood lymphocytes called TCR gamma delta has been identified. The TCR gamma delta appears to act as a receptor capable of mediating triggering of gamma delta T cells. However, it is unknown if the TCR gamma delta recognizes foreign antigens in the context of restriction elements, analogous MHC class I and II antigens. Similarly, the relationship between TCR gamma delta gene segment usage and antigen recognition has not been defined. Therefore, the applicant proposes to generate functional antigen-specific and stimulator cell surface protein-specific TCR gamma delta+ lymphocytes lines and clones by repetitively stimulating TCR gamma delta peripheral blood lymphocytes with haptenated autologous peripheral blood mononuclear cells, with allogeneic cells, and with tumor cell lines. The TCR gamma delta+ lymphocyte lines and clones will then be analyzed functionally to determine if they respond specifically to antigen(hapten) and/or to stimulator cell surface proteins. The V, D, and J gene segments used by the TCR gamma and delta genes expressed on these lines and clones will be evaluated to determine the relationship of gene segment usage to antigen specificity and to recognition of TCR gamma delta target cell surface proteins. Finally, a screening of patients with immunologic abnormalities will be initiated, in order to identify patients with abnormalities in TCR gamma delta+ lymphocyte function or receptor structure. The TCR gamma delta receptors from such patients will be characterized at the protein and gene level.