An inappropriate immune response towards microbial flora in genetically predisposed individuals results in inflammatory bowel disease (IBD). The pathogenic response in IBD is driven by CD4+TH17. Immunoregulatory mechanisms that prevent or counter IBD typically rely on Tregs and IL-10. However, recent studies have identified the involvement of intraepithelial CD4+CD8+T cells in the regulation of intestinal inflammation. Here, we have identified a novel molecular interaction between CRTAM on intestinal T cells and CADM1 on intestinal DC and demonstrated that this interaction is required for intraepithelial CD4+CD8+T cells in the steady-state and for TH17 responses during T. gondii parasitic infection. These results mandate further investigation of the impact of CRTAM-CADM1 interactions on intestinal immunity and their potential exploitation for IBD therapy. In Aim 1, we propose experiments to distinguish whether CRTAM-CADM1 interactions act: a) exclusively in the gut mucosa to facilitate the retention of CD4+T cells and CD4+CD8+ T cells, or b) in the mesenteric lymph nodes to promote priming of CD4+T cells and the acquisition of gut homing molecules. Aim 2 is based on the observation that CD4+CD8+ T cells are absent in germ-free mice, whereas short chain fatty acids (SCFA) induce their expansion. Thus, we will investigate the mechanisms by which the microbiota induces the differentiation of CD4+CD8+T cells and ask whether these mechanisms involve CRTAM-CADM1 interaction. CD4+CD8+T cells may require presentation of commensal antigens by intestinal CADM1+DCs. Alternatively, commensal microbiota may release metabolites that facilitate CD4+CD8+T cell differentiation, possibly by acting as histone deacetylase (HDAC) inhibitors that impact the epigenetics of CD4+CD8+T cell progenitors or CADM1+DCs. In Aim 3, we will explore the mechanisms for the CRTAM-CADM1 dependency of TH17 responses to T. gondii: we will determine whether TH17 cells detected during T. gondii infection are directed toward translocated commensals or are specific for T. gondii and whether CRTAM-CADM1 interactions impact TH17 response to commensals in general. Given the emerging importance of CD4+CD8+T cells in the regulation of intestinal immunity, the relevance of TH17 responses to autoimmunity and the need to manipulate these cells for therapy, this proposal to study CRTAM-CADM1 interactions embodies a new perspective in intestinal immunity that is highly innovative and relevant to IBD.