Innate lymphoid cells (ILCs) including lymphoid tissue-inducer (LTi) cells, IL-22-producing NKp46 + innate cells and IL-13-producing nuocytes play important roles in regulating intestinal microbiota, defence against pathogens and formation of lymphoid tissue [1][2][3][4] . Their development is dependent on Id2 and Rorγt or Rorα 5-7 . Lineage tracing experiments have shown that the common lymphoid precursor gives rise to nuocytes, LTi cells and NKp46 + ILCs 6,8,9 , but these studies have not deciphered the discrete steps and transcription factors that specify ILC subset development, activation and maintenance. Whether NKp46 + ILCs arise directly from LTi cells, or rather represent a separate lineage that diverges earlier in development, remains controversial [10][11][12] . We investigated the requirement for the transcriptional master regulator T-bet (encoded by Tbx21) which is critical for the development of both T cells and NK cells 13,14 , in driving differentiation of ILC populations. Here we report that T-bet played an essential role for the development of NKp46 + ILCs, but was dispensable for LTi cells or nuocytes. Tbx21 +/+ LTi cells adopted an NKp46 + phenotype in vitro and in vivo but not in the absence of Tbx21. Decrease of T-bet expression coordinately reduced Notch1 and Notch2 and we show Notch signaling is necessary for the transition of LTi cells into NKp46 + ILCs. In addition, Tbx21 −/− mice have an accumulation in CD4 − LTi cells and differentiation into NKp46 + ILCs came solely from this population. Our results pinpoint T-bet as the critical regulator of NKp46 + ILC differentiation by regulation of Notch2 signaling. NKp46 + cells are an important element of the protective intestinal mucosal cellular arsenal, and here, we uncover the distinct molecular pathways that guide the development of NKp46 + ILCs. Supplementary Information is linked to the online version of the paper at www.nature.com/nature. Author InformationThe authors declare no competing financial interests. Europe PMC Funders GroupAuthor Manuscript Nat Immunol. Author manuscript; available in PMC 2014 July 01. Supplementary Fig. 2).Analysis of T-bet expression in innate lymphocyte populations by intracellular staining and mRNA levels revealed high expression of T-bet in both NKp46 + ILCs and NK (lin − Rorγt − NKp46 + NK1.1 + ) cells isolated from the intestine, while T-bet was not expressed in LTi cells (Fig. 1c). The related T-box factor Eomes, that performs similar functions to Tbet in CD8 + T cells and NK cells, was not expressed in NKp46 + ILCs or LTi cells ( Supplementary Fig. 3a). Thus, T-bet appears to play a crucial role in the development of NKp46 + ILCs. Similar to T-bet, Blimp1 (encoded by Prdm1) was strongly differentially expressed between LTi and NKp46 + ILC populations ( Supplementary Fig. 3b). However, mice homozygously deficient for Blimp1 (Blimp1 gfp/gfp ) did not show any apparent defect in the development of ILC subsets ( Supplementary Fig. 3c). Thus, Blimp1 is dispensable for ILC differentiation while T-b...

Loss of Nfil3 selectively reduces Peyer’s patch formation, impairing recruitment and distribution of lymphocytes and compromising immune responses to inflammatory and infectious agents.

The cytokine IL-15 is required for natural killer (NK) cell homeostasis; however, the intrinsic mechanism governing this requirement remains unexplored. Here we identify the absolute requirement for myeloid cell leukaemia sequence-1 (Mcl1) in the sustained survival of NK cells in vivo. Mcl1 is highly expressed in NK cells and regulated by IL-15 in a dose-dependent manner via STAT5 phosphorylation and subsequent binding to the 3 0 -UTR of Mcl1. Specific deletion of Mcl1 in NK cells results in the absolute loss of NK cells from all tissues owing to a failure to antagonize pro-apoptotic proteins in the outer mitochondrial membrane. This NK lymphopenia results in mice succumbing to multiorgan melanoma metastases, being permissive to allogeneic transplantation and being resistant to toxic shock following polymicrobial sepsis challenge. These results clearly demonstrate a non-redundant pathway linking IL-15 to Mcl1 in the maintenance of NK cells and innate immune responses in vivo.