Syk signaling in dendritic cells instructs steady-state IL-17 and IL-22 cytokine expression in the intestinal tract

The cytokines interleukin 17 (IL-17) and IL-22 play an important role in host protection in barrier tissues against certain pathogens. More recently, they have emerged as key players in steady state to maintain the barrier function of the intestinal epithelium and to prevent systemic dissemination of commensal bacteria. Although IL-17 and IL-22 production is directly controlled by the presence of microbial components, the mechanism of regulation and the involved host response pathways remain unknown. Here we show that dendritic cells (DCs) are critical for coordinating the production of IL-17 and IL-22 via a Syk-coupled pathway that induces a bimodal activation of IL-17 and IL-22 expression in intestinal T cells and innate lymphoid cells, which involves IL-6 and IL-23p19 respectively. Defects in this pathway result in diminished antimicrobial defense and in impaired systemic immune function as a consequence of defective IL-17 and IL-22 induction. Thus, Syk-mediated signaling in DCs orchestrates intestinal and systemic immune homeostasis via the regulation of IL-17 and IL-22.