Specific Subset of Dendritic Cells Control the Priming of Mucosal Th17 Cells

Abstract

Abstract Phagocytic mononuclear cells play an essential role in regulating gut immune homeostasis by sensing, internalizing microbial parts, and subsequently driving adaptive response in an antigen- and cytokine-dependent context. In a healthy host, physiological Th17 cells are predominantly generated in the gut, induced by local commensal microbiota. However, the precise subpopulation of antigen-presenting cells responsible for imprinting Th17 program in naïve CD4 T cells have not yet been definitively identified. Objective Mapping the functional subset of Th17-inducing dendritic cells (DCs) will uncover new targets for mucosal vaccine design. Methods & Results Using transgenic CD4 T cells specifically recognizing a gut-colonizing commensal bacterial antigen, we found that migratory DCs (CD11chiMHCIIhiZbtb46+) in the mesenteric lymph nodes are indispensable for the initial Th17 cell priming. Whereas the absence of CD103+ or CX3CR1+ DCs did not impact Th17 cell differentiation. Single cell RNA sequencing revealed that the migratory DCs are highly heterogeneous and consist of 8 clusters of transcriptionally specialized subsets. Interleukin-6, the Th17-polarizing cytokine, is expressed by a minor population of DCs with a type I interferon signature. Our results indicate that during homeostasis, Th17 cells activation in the mesenteric lymph nodes and later persistence in the small intestine may be controlled and sustained by different groups of antigen-presenting cells. The complexity and heterogeneity of mucosal DCs imply that other effector and regulatory T cell responses may be regulated by different DC subsets at this unique tissue environment.