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

Abstract

Intestinal immunity is coordinated by specialized mononuclear phagocyte populations, constituted by a diversity of cell subsets. Although the cell subsets constituting the mononuclear phagocyte network are thought to be similar in both small and large intestine, these organs have distinct anatomy, microbial composition, and immunological demands. Whether these distinctions demand organ-specific mononuclear phagocyte populations with dedicated organ-specific roles in immunity are unknown. Here we implement a new strategy to subset murine intestinal mononuclear phagocytes and identify two novel subsets which are colon-specific: a macrophage subset and a Th17-inducing dendritic cell (DC) subset. Colon-specific DCs and macrophages co-expressed CD24 and CD14, and surprisingly, both were dependent on the transcription factor IRF4. Novel IRF4-dependent CD14+CD24+ macrophages were markedly distinct from conventional macrophages and failed to express classical markers including CX3CR1, CD64 and CD88, and surprisingly expressed little IL-10, which was otherwise robustly expressed by all other intestinal macrophages. We further found that colon-specific CD14+CD24+ mononuclear phagocytes were essential for Th17 immunity in the colon, and provide definitive evidence that colon and small intestine have distinct antigen presenting cell requirements for Th17 immunity. Our findings reveal unappreciated organ-specific diversity of intestine-resident mononuclear phagocytes and organ-specific requirements for Th17 immunity.

Dendritic cell functions in the inductive and effector sites of intestinal immunity

“…In addition, F4/80 and CD64 are specific macrophage markers that can be used to distinguish cDCs from macrophages in the LP 17,19 but not in PP where they are not expressed on macrophages (Table 1) 13,15 . It should be noted that CD64 appears also absent from a minor population of macrophages in the colonic LP 20 and has been shown to be expressed by a subset of lung cDCs under inflammatory conditions 21 . Although such inflammatory cDCs have not yet been detected in the intestine, these observations necessitate caution when using CD64 alone as a definitive macrophage marker.…”

“…This ratio is reversed in the colonic LP where CD103 − cDC2s form the majority of the cDC2 compartment 18 . Recently, an additional subpopulation of colonic LP cDC2s has been identified based on the expression of CD26 and CD14 20 .…”