Friday, April 26, 2024
4/26/2024
Project Summary The highly specialized intestinal immune system is charged with maintaining tolerance to harmless stimuli from commensal bacteria and food, while providing protective immunity against pathogens. Dysregulation of this critical balance can lead to inflammatory bowel disease, food allergy, or increased susceptibility to enteric pathogens. CD4+ T cells are key players in intestinal homeostasis, finely tuning responses at the level of antigen recognition and functional differentiation. In the intestinal epithelium (IE) and underlying lamina propria (LP), tissue adapted pro-inflammatory (ie. Th17, Th1) and regulatory (Treg) and intraepithelial (CD8aa+ CD4IEL) CD4+ T cells coordinate immunity and tolerance to diverse intestinal stimuli. Nevertheless, it remains to be defined how TCR repertoire and its specificity translate to function of both LP and IELs in response to microbial antigens. Additionally, very little is known about the characteristics of dietary antigen-specific intestinal T cells. Oral tolerance, a critical mechanism of gut homeostasis whereby oral administration of antigen results in both local and systemic tolerance to that antigen, is known to depend on Tregs. However, the clonal dynamics of polyclonal T cell responses in the setting of tolerance remain unclear. Finally, outside the context of immunization or allergy, T cells that specifically recognize food protein have yet to be identified. Based on data recently published as well as preliminary data obtained during the current funding cycle, we hypothesize that tissue cues combined with TCR-driven signals from commensal microbes and food dictate intestinal T cell functional differentiation in steady state, while disruption of normal T cell responses by infections or allergens results in inappropriate clonal dynamics including expansion of pathological T cells. Aim 1 will define how stimulation by microbiota or enteric viruses impact TCR repertoire and functional differentiation of intestinal CD4 T cells. Aim 2 will characterize the role of dietary antigens in the context of tolerance, enteric infections, or food allergy, affect TCR repertoire and functional differentiation of intestinal CD4 T cells. We combine single cell transcriptomics with a novel fate- mapping strategy to selectively label peripheral T cells that are recruited to the intestine under various microbial and dietary challenges. A recently developed LIPSTIC tool that allows intestinal epithelial cells (IECs) labeling of interacting cells will be utilized to define potential mechanisms of IEL recruitment/expansion in response to nonself stimuli. Recently generated murine strains with fixed TCR Vb chain, or that carry microbiota-specific TCRs, combined with complementary tetramer and gnotobiotic strategies will be used to specifically track and define recognition properties during T cell migration and differentiation in the gut. Novel “super-tetramer” and dietary manipulations, combined with inflammatory challenges will be used to define food antigen-specific T cells during steady state and how intestinal CD4+ T cell responses to dietary antigen are altered in a food allergic or infection context. By combining these innovative approaches and concepts in mucosal immunology, this proposal will help better defining the role of nonself antigen stimulation in T cell repertoire and function in the intestine.
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