This competing renewal application seeks to extend a paradigm that places the epidermal keratinocyte in a central role Th the recruitment and maintenance of T cell infiltration into skin. During the first funding cycle. the principal investigator identified a series of novel cytokines produced by keratinocytes and attempted to integrate them into coherent models of cutaneous inflammation. Such models have been fundamentally intestable in vivo, however, until very recently. In this application, an approach will be used involving transgenic mice constructed so as to express different cytokines and adhesion molecules in epidermis. In this fashion, hypotheses that epidermal cytokines and adhesion molecules are involved in certain types of inflammation can be tested experimentally with scientific rigor. The present proposal will focus on interactions between T cells and keratinocytes, and has evolved to incorporate not only cytokines produced by keratinocytes that influence T cells, but also keratinocyte adhesion molecules that bind to T cell surface molecules and can costimulate T cells. Using a keratin 14 (basal keratinocyte) promoter, we have made transgenic mice that constitutively express ICAM-1, B7, and lL-7 in epidermis; the first two molecules are important in T cell costimulation, and the third is a potent T cell growth factor. Each of these molecules has been reported to be expressed under certain conditions by keratinocytes in vitro and in vivo.
Three aims are proposed. In the first, the role of B7 and ICAM- 1 expression on keratinocytes in the capacity of keratinocytes to activate T cells in vivo and in vitro will be studied. In the second, the ability of constitutive epidermal production of IL- 7, coupled with secondary stimuli, to recruit and sustain a T cell infiltrate will be studied. In the third, the capacity of these transgenes expressed by experimentally induced keratinocytederived neoplasms to elicit a T cell mediated anti-tumor response will be evaluated. These questions, which can only be answered in our transgenic system, will provide important insights into the relationship between keratinocytes, T cells, and skin disease.
