Th17 immunity in the colon is controlled by two novel subsets of colon-specific mononuclear phagocytes

Abstract

Abstract Immune responses in the intestine are coordinated by specialized populations of mononuclear phagocytes. Although the functions of intestine-resident mononuclear phagocytes and the different cell subsets that constitute these populations are thought uniform across the entire intestine, it is clear that the anatomy, microbes, and immunological demands are distinct for small and large intestine. Whether these distinctions also include organ-specific mononuclear phagocyte populations, or that these have organ-specific roles in immunity are unknown. Here we identify two novel subsets of colon-specific mononuclear phagocytes, a dendritic cell (DC) subset and a macrophage subset, both of which are exclusive to the colon and are not found in small intestine. These colon-specific DCs and macrophages co-expressed CD14 and CD24, markers which are generally singularly expressed by intestinal DCs and macrophages and commonly used to distinguish between these two cell types. Colon-specific CD14+CD24+ DCs and macrophages failed to express macrophage markers CX3CR1, F4/80, CD64 and CD88, and surprisingly, both the DC and macrophage subset were dependent on the transcription factor IRF4. We further find that colon and small intestine have distinct antigen presenting cell (APC) requirements for Th17 immunity and that while colon-specific CD14+CD24+ APCs were essential for Th17 immunity in the colon, this role in small intestine was mediated by different APC subsets. Our findings reveal unappreciated organ-specific diversity of intestine-resident mononuclear phagocytes and organ-specific requirements for Th17 immunity.