Microbial Flora Drives Interleukin 22 Production in Intestinal NKp46⁺ Cells that Provide Innate Mucosal Immune Defense

Natural killer (NK) cells are innate lymphocytes with spontaneous antitumor activity, and they produce interferon-γ (IFN-γ) that primes immune responses. Whereas T helper cell subsets differentiate from naive T cells via specific transcription factors, evidence for NK cell diversification is limited. In this report, we characterized intestinal lymphocytes expressing the NK cell natural cytotoxicity receptor NKp46. Gut NKp46⁺ cells were distinguished from classical NK cells by limited IFN-γ production and absence of perforin, whereas several subsets expressed the nuclear hormone receptor retinoic acid receptor-related orphan receptor t (RORγt) and interleukin-22 (IL-22). Intestinal NKp46⁺IL-22⁺ cells were generated via a local process that was conditioned by commensal bacteria and required RORγt. Mice lacking IL-22-producing NKp46⁺ cells showed heightened susceptibility to the pathogen Citrobacter rodentium, consistent with a role for intestinal NKp46⁺ cells in immune protection. RORγt-driven diversification of intestinal NKp46⁺ cells thereby specifies an innate cellular defense mechanism that operates at mucosal surfaces.