Dendritic cells in the intestine: sensing of microbiota and inducing of inflammatory bowel disease

Dendritic cells (DCs) are potent antigen presenting cells (APC) that sense microbes and induce T cell activation and functional differentiation. The APC function of DCs is upregulated by the signaling pathway downstream of the microbial sensing receptor, a process well studied during pathogen infection and immunization. Multiple lines of evidence suggested that DCs in the intestine lamina propria (LP-DCs) frequently interact with the innocuous microbiota, and through these interactions LP-DCs support intestinal immune homeostasis. However, DC responses to microbiota, if not regulated, can give rise to inflammatory T cells and trigger inflammatory bowel disease (IBD). The DC subsets, DC functions and signaling pathways that induce inflammatory T cells remain incompletely characterized. Here, we demonstrated that mice lacking signaling attenuator A20 (A20cko mice) in DCs develop spontaneous small intestine inflammation that is dependent of microbiota, DCs and T cells. LP-DCs induce inflammatory T cells and that the signals perceived and APC functions are unique for three distinct LP-DC subsets. Thus, while CD103+CD11b- DCs exclusively upregulate their ability to instruct IFNγ+ T cells, CD103+CD11b+ DCs exclusively upregulate their ability to instruct IL-17+ T cells. Of note, APC functions of both DC subsets are upregulated in a MyD88-independent fashion. In contrast, CD103-CD11b+ DCs instruct both IFNγ+ and IL-17+ T cells, and only the IL-17-inducing APC functions require MyD88. In disease pathogenesis, both CD103-CD11b+ and CD103+CD11b+ DCs expand pathologic Th17 cells.

Although MyD88 pathways are potent inducer of intestinal inflammation in the colitis of IL-10 knockout mice and upon transferring of naïve T cells into Rag-deficient hosts, MyD88 pathways are not required for the inflammation of small intestine in A20cko mice. Among the MyD88-independent signaling pathways that could mediate host interaction with microbiota, Dectin-1 pathway is of particular interest because both the receptor Dectin-1 and the downstream signaling molecule CARD9 are IBD-associated genes. Additionally, the defect in either molecule influences the severity of the intestinal inflammation in mouse. We established that the production of inflammatory cytokines downstream of the Dectin-1 pathway is restricted by A20. Mechanistically, A20 inhibits TRAF6 ubiquitination downstream of the Dectin-1 pathway, thereby controlling NFκB and Jnk activation. Although we showed that CD103-CD11b+ and CD103+CD11b+ DCs express Dectin-1 and CARD9, the Dectin-1 pathway is not required for the upregulation of DC function and expansion of inflammatory T cells in the intestine of A20cko mice. Thus, our studies have unveiled a critical role of MyD88-independent pathways in mediating the interaction of the microbiota and LP-DCs. MyD88-independent pathway is capable of driving functional maturation of LP-DCs, pathological expansion of CD4 T cells, and the inflammatory disease in the small intestine.