Crohn’s disease (CD), a form of idiopathic inflammatory bowel diseases (IBD), results from uncontrolled T-helper
(Th) cell responses to intestinal commensal bacteria in genetically susceptible hosts. While the pathogenic role
of Th17 cells in CD patients is controversial, many studies have shown an increase in Th17 cells in intestinal
mucosa of CD. Blocking IL-17A, a signature cytokine of Th17 cells, was not effective in clinical studies. This may
be due to functional heterogeneity and dynamic plasticity of Th17 cells, especially as it is now understood that
some Th17 cells are required for homeostatic maintenance at mucosal surfaces, while others are extremely
proinflammatory and pathogenic. However, the mechanism regulating the complexity of Th17 cells in intestinal
mucosa is unknown. Our objective in this application is to determine the mechanisms regulating the inflammatory
capacity of intestinal Th17 cells in patients with CD. In a recent study we found that receptor-interacting protein
2 (Rip2) deficient T cells preferentially differentiated towards Th17 when exposed to pathogenic conditions (IL-
1ß, IL-23, IL-6). Additionally, in a preliminary study using the TNBS model of colitis, Rip2-/- mice developed a
severe ileitis with an increased accumulation of Th17 T-cells in the ileum. Many of these Th17 cells were also
expressing IFN-¿. These IL-17A+ IFN-¿+ (Th17/Th1) cells express CCR9, a chemokine receptor that allows them
to migrate to the ileal mucosa. In in vitro studies we observed that RIP2 deficient T-cells preferentially develop
into these highly pathogenic Th17/Th1. These findings are clinically relevant as mutations of Rip2 have been
associated with CD. We have also found that the Rip2 CARD domain can inhibit pathogenic Th17 differentiation
and in preliminary studies, induce conventional Th17 development, thus potentially offering the possibility as a
therapeutic intervention. Therefore, we wish to address the hypothesize that impaired Rip2 signaling in T
cells causes ileal inflammation by promoting the formation and infiltration of Th17/Th1 double positive
inflammatory T-cells. Our innovative approaches using robust animal models and in vitro generation of Th cells
that are responsive to intestinal commensal bacteria will allow us to fill the current knowledge gap between Th17
cell biology and the pathogenesis of CD in the context of host response to intestinal commensal bacteria. We
have also found in preliminary studies that the Rip2 CARD domain can inhibit pathogenic Th17 differentiation
and may offer the possibility as therapeutic intervention. Our hypothesis will be addressed via the following
Specific Aims: 1) Determine the function of T cell intrinsic Rip2 in the generation and infiltration of pathogenic
Th17/Th1 cells that cause ileal inflammation. 2) Determine the therapeutic potential of the Rip2 CARD Domain
in ileal inflammation. Understanding the mechanisms regulating intestinal Th17 inflammation may lead to novel
pharmacological interventions and innovative approaches in the management of CD patients with ileal
involvement.