IBD is a chronic autoimmune disease of the gut affecting millions of people worldwide . Several studies over the past decade using mouse model of colitis and human IBD samples have established the central role for antigen presenting cells and CD4 T cells in induction and regulation of intestinal inflammation . Under normal physiological conditions APCs continuously monitor GI tract and maintain mucosal homeostasis through strong induction of regulatory T cell responses. However, in IBD patients, the intestinal dysbiosis and break in intestinal epithelial barrier lead to activation of gut resident APCs and T cells that initiate IBD pathology. Therefore targeting regulatory signaling in APCs and T cells could help restore the immune homeostasis at site of inflammation and offer a novel therapeutic replacement for currently available broad spectrum immunosuppressive drugs.
The current project interrogates the effect of targeting immune regulatory signals in APCs and T cells using 2 following approaches and its impact on immune tolerance:
• Regulating -catenin signaling in CD4 T cells to restore immune tolerance during IBD: Recently published studies and our in-house data indicate that activation of Wnt/β-catenin signaling in DCs and terminally differentiated CD4 T cells induces strong immunoregulatory phenotype. Project hypothesizes that the activation of β-catenin pathway during naïve CD4 T cell differentiation promote Treg and induce strong immune tolerance and suppress auto-immune pathologies.
• Fine tuning the immune inhibitory receptor signal on antigen presenting cells to induce immune tolerance during inflammation: Immune inhibitory receptors are a class of surface receptors that keeps the unwanted immune responses under check to avoid autoimmunity, while maintaining full potential to combat infection and cancer. The project proposes to understand the signaling dynamics of these receptors in APC and modulate the signals to fine-tune the APCs to induce tolerance.