Regulated Expression of Nuclear Receptor RORγt Confers Distinct Functional Fates to NK Cell Receptor-Expressing RORγt+ Innate Lymphocytes

Whether the recently identified innate lymphocyte population coexpressing natural killer cell receptors (NKRs) and the nuclear receptor ROR gamma t is part of the NK or lymphoid tissue inducer (LTi) cell lineage remains unclear. By using adoptive transfer of genetically tagged LTi-like cells, we demonstrate that NKR-ROR gamma t(+) innate lymphocytes but not NK cells were direct progenitors to NKR+ROR gamma t(+) cells in vivo. Genetic lineage tracing revealed that the differentiation of LTi-like cells was characterized by the stable upregulation of NKRs and a progressive loss of ROR gamma t expression. Whereas interleukin-7 (IL-7) and intestinal microbiota stabilized ROR gamma t expression within such NKR-LTi cells, IL-12 and IL-15 accelerated ROR gamma t loss. ROR gamma t(+) NKR-LTi cells produced IL-22, whereas ROR gamma t(-) NKR-LTi cells released IFN-gamma and were potent inducers of colitis. Thus, the ROR gamma t gradient in NKR-LTi cells serves as a tunable rheostat for their functional program. Our data also define a previously unappreciated role of ROR gamma t(-) NKR-LTi cells for the onset or maintenance of inflammatory bowel diseases.