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.
Inflammatory bowel disease (IBD) is a major cause of disease worldwide. Excessive activation of the immune system associated with the gastrointestinal tract plays a crucial role in IBD. In this grant, we will focus on new molecules that we have identified in the gut of humans and mice and will determine how they control the intestinal immune response. We believe that these molecules may be a potential target for therapy of IBD and other intestinal diseases.
