Regulation and function of nonlymphoid organ CD103+ dendritic cells

项目总结/文摘

PROJECT SUMMARY/ABSTRACT Dendritic cells (DCs) comprise critical antigen (Ag) presenting immune cells, which are important for regulating adaptive immunity, immune tolerance, immunological memory, and innate responses. The type 1 conventional DC (cDC1) subset is highly proficient in Ag cross-presentation on major histocompatibility complex class I (MHC-I) and induction of CD8+ T lymphocytes specific for extracellular Ag. Accordingly, significant effort has been applied toward understanding roles for cDC1s in anti-tumor immunity. By contrast, major gaps in knowledge center on cDC1 function in peripheral tissues such as the gastrointestinal (GI) tract. In the first project period of this award, we discovered key immune-regulatory functions for the cytokine-activated signal transducer and activator of transcription 3 (STAT3) in cDC1s. Our work also revealed a protective role for STAT3 in CD11c+ cells, comprising multiple Ag-presenting subsets including cDC1s. We showed STAT3- deficiency in CD11c+ cells cooperates with therapeutic T cell activation by anti-cytotoxic T-lymphocyte- associated protein 4 (CTLA-4) blockade to drive severe intestinal inflammation and tissue destruction. Furthermore, we found STAT3-deficiency in CD11c+ cells influences the composition and complexity of the intestinal microbiome. Using a novel model to delete STAT3 in cDC1s, we recently showed STAT3 restrains cDC1-mediated GI inflammation. Taken together, our results suggest cDC1s control intestinal inflammatory responses and mediate key interactions with the host microbiome via STAT3-intrinsic mechanisms, yet major gaps in knowledge center on the contribution of cDC1s to intestinal immunity and inflammation, or how this population is modulated by or affects the commensal microbiota. To address these gaps, we will test the central hypothesis that cDC1s direct intestinal immune responses to maintain homeostasis; overactivation of cDC1s by loss of STAT3 potentiates intestinal inflammation in homeostasis or upon challenge with immune- activating stimuli (e.g., CTLA-4, infection) and disrupts the commensal microbiota. This hypothesis will be examined in three aims: 1) Delineate roles for cDC1s and cDC1-intrinsic STAT3 in colon inflammation and response to CTLA-4 therapy; 2) Determine the consequences of cDC1- and cDC1-intrinsic STAT3-deficiency upon T cell generation and T cell activity in the colon; and 3) Evaluate the interaction of cDC1s and cDC1- intrinsic STAT3 with the gut microbiome and control of GI pathogen-driven inflammation. Completion of this project will reveal key facets of intestinal immunity that are currently unknown, including the contribution of cDC1s to intestinal immunity and roles for cDC1-intrinsic STAT3 in these responses. Our studies will provide new basic insights into cDC1 biology and may aid in identifying approaches to mitigate intestinal inflammatory disorders or immune-related adverse events (irAEs) associated with CTLA-4 immune checkpoint blockade.