NKp46+CD3- natural killer lymphocytes isolated from blood, lymphoid organs, lung, liver and uterus can produce granule-dependent cytotoxicity and interferon-gamma. Here we identify in dermis, gut lamina propria and cryptopatches distinct populations of NKp46+CD3- cells with a diminished capacity to degranulate and produce interferon-gamma. In the gut, expression of the transcription factor RORgammat, which is involved in the development of lymphoid tissue-inducer cells, defined a previously unknown subset of NKp46+CD3- lymphocytes. Unlike RORgammat- lamina propria and dermis natural killer cells, gut RORgammat+NKp46+ cells produced interleukin 22. Our data show that lymphoid tissue-inducer cells and natural killer cells shared unanticipated similarities and emphasize the heterogeneity of NKp46+CD3- cells in innate immunity, lymphoid organization and local tissue repair.

NKp46 is a cell surface receptor expressed on natural killer (NK) cells, on a minute subset of T cells, and on a population of innate lymphoid cells that produce

The gut is a major barrier against microbes and encloses various innate lymphoid cells (ILCs), including two subsets expressing the natural cytotoxicity receptor NKp46. A subset of NKp46 þ cells expresses retinoic acid receptor-related orphan receptor gt (RORgt) and produces IL-22, like lymphoid tissue inducer (LTi) cells. Other NKp46 þ cells lack RORgt and produce IFN-g, like conventional Natural Killer (cNK) cells. The identity, the regulation and the in vivo functions of gut NKp46 þ ILCs largely remain to be unravelled. Using pangenomic profiling, we showed here that small intestine (SI) NKp46 þ RORgt À ILCs correspond to SI NK cells. Conversely, we identified a transcriptional programme conserved in fetal LTi cells and adult SI NKp46 þ RORgt þ and NKp46 À RORgt þ ILCs. We also demonstrated that the IL-1b/IL-1R1/MyD88 pathway, but not the commensal flora, drove IL-22 production by NKp46 þ RORgt þ ILCs. Finally, oral Listeria monocytogenes infection induced IFN-g production in SI NK and IL-22 production in NKp46 þ RORgt þ ILCs, but only IFN-g contributed to control bacteria dissemination. NKp46 þ ILC heterogeneity is thus associated with subset-specific transcriptional programmes and effector functions that govern their implication in gut innate immunity.