Goblet cells regulate expansion of colonic iNKT cells in CD1d-dependent manner

Abstract

Abstract Invariant natural killer T (iNKT) cells are innate-like T cells that secrete a wide array of cytokines and immune mediators. These cells recognize self or microbial ligands presented by cells expressing CD1d, and can contribute to host protection or/and pathogenesis during intestinal inflammation. The colonic iNKT cell population is established in early life under the influence of the microbiota and current understanding is that this iNKT cells are not manipulable in later life. Previous studies have identified that goblet cell associated passages (GAPs) play a role in luminal antigen delivery and the induction and maintenance of peripherally induced T regulatory cells in the steady state. Colonic GAPs are largely absent in adult mice due to goblet cell (GC) microbial sensing, which inhibits GAP formation. We hypothesized, that when present, colonic GAPs may deliver glycolipids to stimulate colonic iNKT cells. We found that the glycolipids can be delivered through GAPs and that inducing colonic GAPs in adult mice using pharmacological inhibitors or transgenic mouse models resulted in significant iNKT cell expansion. Further deletion of CD1d on GCs inhibited iNKT cell expansion suggesting a role for colonic GCs in presenting glycolipids to iNKT cells. Single cell RNA sequencing of sorted colonic iNKT cells showed significantly expanded iNKT2 and iNKT1 subsets after colonic GAP induction. Furthermore, the iNKT cells expanding after opening colonic GAPs were protective in DSS-induced colitis. Our findings suggest that the GAP function and CD1d expression by GCs plays a role in modulating colonic iNKT cell subsets in adulthood and can be protective in some colitis models.