IL-7 and IL-15 independently program the differentiation of intestinal CD3^-NKp46⁺ cell subsets from Id2-dependent precursors

The natural cytotoxicity receptor NKp46 (encoded by Ncr1) was recently shown to identify a subset of noncytotoxic, Rag-independent gut lymphocytes that express the transcription factor Rorc, produce interleukin (IL)-22, and provide innate immune protection at the intestinal mucosa. Intestinal CD3 ^-NKp46⁺ cells are phenotypically heterogeneous, comprising a minority subset that resembles classical mature splenic natural killer (NK) cells (NK1.1⁺, Ly49⁺) but also a large CD127 ⁺NK1.1^- subset of lymphoid tissue inducer (LTi)-like Rorc⁺ cells that has been proposed to include NK cell precursors. We investigated the developmental relationships between these intestinal CD3 ^-NKp46⁺ subsets. Gut CD3^-NKp46⁺ cells were related to LTi and NK cells in requiring the transcriptional inhibitor Id2 for normal development. Overexpression of IL-15 in intestinal epithelial cells expanded NK1.1⁺ cells within the gut but had no effect on absolute numbers of the CD127⁺NK1.1^-Rorc+ subset of CD3^-NKp46⁺ cells. In contrast, IL-7 deficiency strongly reduced the overall numbers of CD3^-NKp46⁺NK1. 1^- cells that express Rorc and produce IL-22 but failed to restrict homeostasis of classical intestinal NK1.1⁺ cells. Finally, in vivo fate-mapping experiments demonstrated that intestinal NK1.1 ⁺CD127^- cells are not the progeny of Rorc-expressing progenitors, indicating that CD127⁺NK1.1^-Rorc⁺ cells are not canonical NK cell precursors. These studies highlight the independent cytokine regulation of functionally diverse intestinal NKp46 ⁺ cell subsets.