RORγt+ innate lymphoid cells regulate intestinal homeostasis by integrating negative signals from the symbiotic microbiota

The transcription factor RORγt is expressed in many cell types. Eberl and colleagues show that intestinal homeostasis is regulated by an IL-25-dependent feedback pathway involving IL-22-expressing RORγt+ innate lymphoid cells. Lymphoid cells that express the nuclear hormone receptor RORγt are involved in containment of the large intestinal microbiota and defense against pathogens through the production of interleukin 17 (IL-17) and IL-22. They include adaptive IL-17-producing helper T cells (TH17 cells), as well as innate lymphoid cells (ILCs) such as lymphoid tissue–inducer (LTi) cells and IL-22-producing NKp46+ cells. Here we show that in contrast to TH17 cells, both types of RORγt+ ILCs constitutively produced most of the intestinal IL-22 and that the symbiotic microbiota repressed this function through epithelial expression of IL-25. This function was greater in the absence of adaptive immunity and was fully restored and required after epithelial damage, which demonstrates a central role for RORγt+ ILCs in intestinal homeostasis. Our data identify a finely tuned equilibrium among intestinal symbionts, adaptive immunity and RORγt+ ILCs.