gammadelta+ T cells are found in all vertebrates examined. They reside in the thymus, secondary lymphoid organs, and epithelial layers, and display some functions common to alphabeta T cells, including cytolytic activity and lymphokine production. While their physiological functions remain to be defined, it is highly likely gammadelta cells play an important role(s) in immunity. An understanding of these roles requires considerable further information concerning their specificity and function. In addition the gammadelta receptor system can serve as a relatively simple system to evaluate the regulation of antigen receptor gene rearrangement and expression in general. Two general issues concerning the immunobiology of gammadelta cells are addressed in this proposal. The first concerns the important question whether MHC molecules play a role in restricting recognition by gammadelta cells or in the maturation of gammadelta cells in ontogeny. To explore this issue we propose to analyze gammadelta cell differentiation, function and recognition in unique mutant mice that lack beta2-microglobulin expression, and hence fail to functionally express class 1 MHC molecules. The second issue addressed pertains to the highly ordered ontogenic regulation of the intrathymic production of subtypes of gammadelta cells that express different Vgamma/Vdelta genes, are destined for distinct peripheral localization, and presumably recognize distinct sets of physiological ligands. The existing data suggest that molecular mechanisms target specific sets of V genes for rearrangement at different stages in ontogeny. We propose to test this model directly, and define relevant target sequences, with the use of mice transgenic for defined rearrangement substrates. In addition, further analysis of gamma enhancer and negative regulatory elements is to be addressed.
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