Selective IL-27 production by intestinal regulatory T cells permits gut-specific regulation of TH17 cell immunity

Regulatory T cells (Tregcells) are instrumental in establishing immunological tolerance. However, the precise effector mechanisms by which Tregcells control a specific type of immune response in a given tissue remains unresolved. By simultaneously studying Tregcells from different tissue origins under systemic autoimmunity, in the present study we show that interleukin (IL)-27 is specifically produced by intestinal Tregcells to regulate helper T17 cell (TH17 cell) immunity. Selectively increased intestinal TH17 cell responses in mice with Tregcell-specific IL-27 ablation led to exacerbated intestinal inflammation and colitis-associated cancer, but also helped protect against enteric bacterial infection. Furthermore, single-cell transcriptomic analysis has identified a CD83+CD62LloTregcell subset that is distinct from previously characterized intestinal Tregcell populations as the main IL-27 producers. Collectively, our study uncovers a new Tregcell suppression mechanism crucial for controlling a specific type of immune response in a particular tissue and provides further mechanistic insights into tissue-specific Tregcell-mediated immune regulation.