T cells bearing invariant gammadelta T cell antigen receptors localize to distinct epithelial sites in the adult mouse. The restricted TCR use, fetal thymic origin, and strict tissue localization suggest that these gammadelta T cells may provide a specialized function in the epithelial tissues distinct from that of circulating alphabeta and gammadelta T cells. The goal of the current proposal is to analyze the production of tissue specific cytokines and chemokines by gammadelta T lymphocytes resident in epithelial tissues. We have recently demonstrated that gammadelta T cells residing in the epidermis recognize stressed or damaged skin keratinocytes and respond by the secretion of cytokines and proliferation. One of the cytokines produced by these cells is a keratinocyte specific growth factor, KGF, which plays a role in normal keratinocyte proliferation and in wound healing. T cells isolated from lymphoid organs as well as a panel of T cell clones and hybridomas did not appear to produce this cytokine. This raises the possibility that a function of these cells is to recognize and respond to damaged or malignant cells appearing in the skin by secretion of a factor which allows for timely and localized proliferation. The function and specificity of the gammadelta T cell produced KGF will be tested in models of would healing using mutant mice selectively deficient for KGF. In addition, T cells from other epithelial tissues will be analyzed for their ability to produce KGF that may be involved in maintenance and repair of epithelial cells. The first T cells to appear during thymic development bear gammadelta T cell receptors and are the precursors of the epithelial gammadelta T cells in the adult and thus may be able to produce KGF. For this reason the effects of T cell produced KGF on the fetal thymic microenvironment will also be determined. Our recent finding that epithelial gammadelta T cells inducibly secrete a panel of chemokines suggests that the recruitment of non-resident cell types into sites of epithelial trauma is another potential consequence of gammadelta T cell recognition of antigen. Production of tissue specific cytokines and chemokines by resident lymphocytes supports a role for these cells in immune surveillance, wound repair, and protection from malignancy. These studies should increase our understanding of the physiological role of gammadelta T lymphocytes found in epithelial tissues and their relationship with neighboring cells.
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