MECHANISM OF A FUNCTIONAL SWITCH IN GAMMA DELTA T CELLS

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Recent observations indicate that GammaDelta T cells can undergo a functional switch during the course of disease. We believe that understanding the mechanism of this switch is important because it is probably central to any role these cells play in the regulation of the immune response. In this proposal, our overall objective is to determine what causes GammaDelta T cells to undergo a functional switch. Our specific aims are as follows: Aim 1: to test the hypothesis that responses of different GammaDelta TCR-defined subsets correlate with distinct functions. Using mice infected with the intracellular pathogen Listeria monocytogenes, we plan to examine whether the VGamma1, VGamma4, or VGamma6 subsets show differential cytokine production in infected mice, and to assess how selectively removing each subset affects the disease outcome. Aim 2: to test the hypothesis that functional switching in GammaDelta T cells is controlled by GammaDelta T cells themselves. Here, we will examine whether GammaDelta T cells either directly or indirectly control their own functional switching: 1) by responding as subsets with set functions when triggered by particular antigens or host signals; 2) by stimulating the responses of each other, such that one GammaDelta T cell subset having a set function induces the response of the next, whose set function differs; 3) by inducing FasL-mediated cell death among certain GammaDelta T cells to make way for responses by others having different functions; and 4) by inducing FasL- mediated cell death within other immune cells, thus altering the cytokine milieu and perhaps the subsequent function of GammaDelta T cells as well. Aim 3: to test the hypothesis that the functional switch in GammaDelta T cells is influenced or controlled by external factors. We plan examine the cytokines made by GammaDelta T cells in systems in which the normal cytokine milieu has been perturbed. We will focus on three different ways in which an externally induced switch could occur: 1) as an overall switch in the cytokines produced by GammaDelta T cells of all types; 2) as a subset-based switch in which external cytokines favor the stimulation of certain GammaDelta T cell subsets with a set cytokine profile over other subsets; and 3) via changes in infiltrating inflammatory cells that cause the same cytokines to have different effects, even though no actual switch in cytokines made by the GammaDelta T cells has occurred.