The Basis of Functional Variation in Gamma/Delta T cells

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DESCRIPTION (provided by applicant): One of the most important issues in immunology today involves how immune responses are regulated. A number of cell types, including the (gammadeltaT cells, have been shown to influence immune and inflammatory responses, but little is understood about how this process is carded out. The gammadelta T cells of mice and humans have a quite limited TCR repertoire, and appear to exist largely as subsets of cells having certain conserved TCR elements, often distributed in a nonrandom manner. Our recent studies have indicated that gammadelta T cell subsets also differ functionally from one another. Our hypothesis is that infection or inflammation induces the expression of ligands for particular gammadelta TCRs, which in turn stimulate the responses of functionally distinct gammadelta cell subsets, having diverse effects on the host response. The specific aims of this proposal are to test three major implications of this hypothesis: Specific Aim 1 - to determine whether gammadelta TCR type and function also cosegregate in listeriosis. Our hypothesis implies that gammadelta T cells subsets are functionally distinct from one another. We plan to examine and compare three gammadelta T cell subsets that respond during inflammation induced by Listeria infection for their cytokine profiles, their ability to proliferate during infection, and their ability to modulate macrophage-mediated killing of Listeria. Specific Aim 2 - to examine whether TCR stimulation is required to bring about the response of a gammadelta T cell subset during Listeria infection. Our hypothesis implies that a gammadelta T cell subset must be specifically activated in order to evoke a certain function. If, as we propose, the TCR defines the subset, then TCR stimulation would be critical in bringing about the responses of two gammadelta T cell subsets. We will examine the role of the TCR in eliciting functional responses of two gammadelta T cell subsets using soluble TCR multimers as competetive agents. Specific Aim 3 - to determine the mechanism by which the gammadelta T cell subsets influence disease outcome. Our hypothesis implies that gammadelta T cells subset have fixed functions. Using adoptive transfer, we will examine three gammadelta T cell subsets individually for their ability to influence listerioisis in mice otherwise lacking gammadelta T cells. We will also examine the importance to disease outcome of the ability of each subset to produce particular cytokines, induce the death of other cells, and undergo apoptosis.