ANTIGEN HANDLING AND CYTOKINE PHENOTYPE REGULATION IN NORMAL AND INFLAMED COLON

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The pathogenesis of inflammatory of inflammatory bowel disease (IBD) involves complex interactions among immune, genetic, and environmental factors. Evidence from a growing number of mouse models of IBD support a central role for disregulated CD4 T cell responses to the enteric bacterial flora as a common disease mechanism. While these models have directed attention to specific T cell subpopulations and cytokines as mediators of disease and CD4 T cells resident in mucosal immune tissues, particular the colon. The specific antigen(s) and bacterial populations that initiate and sustain chromic intestinal inflammation are unknown. Similarly, the antigenic specificity and phenotypes of normal and disregulated CD4 T cell population are unknown or poorly characterized. This proposal will examine the initiation and progression of chronic colonic inflammation using an antigen-specific model for study of interactions between clonal CD4 T cell populations with their cognate antigen in the intestine. The well- characterized, ovalbumin (OVA)-specific DO11.10 TCR transgenic mouse model will be used to delineate the mechanism of CD4 T cell recognition and response to free or bacterially associated OVA in the colon, and to determine how specific disruptions of this response lead to colitis. We postulate that turnover of the bacterial flora in the cecum and proximal colon generate three general types of antigens: free, cytosolic and periplasmic antigens released by dying organisms; cell membrane or cell wall associated antigens: free, cytosolic and periplasmic antigens released by dying organisms; cell membrane or cell wall associated antigens released by dying organisms, and intact, viable organisms. Uptake of these different forms of bacterial antigens in the colonic lymphoid follicles, or more distal immune tissues, drive differentiation of distinct lineages of CD4 T cells. Free bacterial antigens are toleragens that favor development of regulatory type (e.g. Th1) cells, whereas membrane associated antigens and live organisms, because they are particulate antigens with phlogistic properties, preferentially induce pro-inflammatory effector CD4 cells (e.g. Th1 cells). It is the mixed nature of the antigenic load handled by the intestinal lymphoid tissues that stimulates differentiation of pro- and anti-inflammatory CD4 T cell phenotypes that maintain homeostasis. In the first aim, we will test the hypothesis that in vivo development of Tr1-type regulatory T cells is induced by recognition of free antigen whereas development of pro-inflammatory effector cells that cause colitis requires recognition of bacterially associated antigen. In the second aim, we will test the hypothesis that in the absence of a regulatory CD4 T cell population, effector CD4 T cells induce an antigen-specific colitis driven by bacterially associated antigen.