Studies with genetically manipulated mouse models of experimental Inflammatory Bowel Diseases (IBD) have lead to an understanding that perturbations of the finely tuned balance between the immune system and the vast antigenic load of the colon can result in disease. Pathogenic CD4+ T cells, Th1 or Th2 depending on the model, accumulate in the lamina propria followed by inflammation of the intestinal mucosa. Bacterial antigens and/or mouse antigens induced by colonic bacteria are presented to the T cells by professional Antigen Presenting Cells (APC). In healthy mice the pathogenic T cells are prevented from expanding, and thus initiating colitis, by CD4+25+ Treg cells. Our preliminary studies show that mice, which lack the cell surface receptor Ly108, are defective in Th2 cell and possibly NKT cell development and Ly108-/- neutrophils are impaired in the killing of bacteria. Based on the phenotype of the Ly108-/- mouse, we propose the central hypothesis that Ly108 signaling is critical for processing commensal bacteria and for T helper cell functions and consequently to the development of chronic colitis. Therefore three questions are being addressed in the proposed experiments: i) will the deletion of Ly108 from APCs, and CD4+ T cells directly or indirectly affect colitis and will a monoclonal antibody directed against Ly108 or a soluble Ly108 ligand (Ly108-Fc) prevent and/or cure experimental colitis, ii) how does Ly108 control T cell signal transduction pathways and iii) how does the cell surface receptor Ly108 influence the bacterial killing mechanism by phagocytes? The experiments proposed in this application are grouped into the following specific aims, which will test the hypothesis that 1. Ly108 on T cells APCs and neutrophils initiates signaling pathways that are involved in the pathogenesis of experimental colitis. 2. Ly108 recruits the src-kinases Fyn or Lck and resident lipid raft proteins to initiate signal transduction in CD4+, CD8+ and NKT cells. 3. the Ly108 receptor regulates bacterial killing in phagocytes. Together these experiments should clarify the interplay between phagocytes, T helper cell and NKT cell controlled pathways to experimental colitis. The results of these studies should suggest therapeutic strategies that can be applied to IBD patients. ? ? ?
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