A break in the tolerance of auto-reactive T cells is an integral part of the pathogenesis of several autoimmune diseases. In addition to reacting to tissue antigens, intestinal T cells are unique in that they must restrict their responsiveness to antigens persistently entering from the lumen. Since T cells recognizing luminal or tissue antigens exist in the intestine, an aberration in the control of their responsiveness/anergy will contribute to the pathogenesis of the autoimmune-like diseases in the gastrointestinal tract. Our data show that anergy in auto-reactive, intestinal T cells is ablated by stimulation with microbial superantigens or cytokines such as IL-2. Moreover during inflammation, epithelial cells express an array of surface molecules that are recognized by T cells and may enhance T cell activation and the maintenance of chronic inflammation. In health, the intestinal epithelial cells exclude antigenic material from the lumen and manifest a pattern of gene expression that selectively signals CD8+ T cells and favors the induction of anergy. In disease, epithelial cells express markedly increased levels of class II MHC molecules and preferentially stimulate and expand the number of activated CD4+ helper T cells. Current data suggest that a decrease in the relative numbers of the Th2 subset of helper T cells or the IL-10 and TGF-beta they produce, leads to an increase in interferon-gamma, an increase in class II MHC expression and the promotion of cell-mediated immunity and chronic colitis. Furthermore, adoptive transfer of as few as 2 X 10/6 CD+ T cells from these mice will cause colitis in recipient animals. Our general hypothesis is that an imbalance in cytokines favoring the induction of Th1 cells leads to the activation of auto-reactive T cells in the intestine in response to stimulation by luminal flora. More specifically, IL-10 plays a critical role in the regulation of intestinal T cell activation by epithelial cells by counter-balancing the proinflammatory effects of cytokines derived from Th1 cell such as interferon-gamma. Our approach will examine the effect of these cytokines on intestinal epithelial cells and their role in antigen presentation including: an evaluation of the role of IL-10 and interferon-gamma in the regulation of surface molecules expressed by cultured or freshly isolated enterocytes; a comparison of T cell reactivity to specific antigens presented by enterocytes treated with these cytokines and; an evaluation of the mechanisms whereby IL-10 inhibits the generation of auto-reactive T cells. This approach will be addressed in the following specific aims: 1. To examine the effect of IL-10 and IFN-gamma on the regulation of antigen presentation by enterocytes. 2. To characterize the expression of IL-10 receptors on enteric epithelium. 3. To determine if the absence of IL-10 impairs the development of tolerance in intestinal T cells. 4. To evaluate the role of interferon-gamma T cell activation and the induction of colitis in vivo. Although the specific, antigenic trigger leading to the various forms of colitis is unknown, the proposed studies permit an examination of the molecular basis for the induction of tolerance or inflammation that will be relevant to several triggers. Clarifying the role of these cytokines controlling auto-reactive T cells will define the pathogenesis of colitis and identify therapeutic strategies that can be applied to these intestinal diseases.
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