The transcription factor T-bet is essential for the development of NKp46+ innate lymphocytes via the Notch pathway

NKp46(+) innate lymphoid cells (ILCs) serve important roles in regulating the intestinal microbiota and defense against pathogens. Whether NKp46(+) ILCs arise directly from lymphoid tissue-inducer (LTi) cells or represent a separate lineage remains controversial. We report here that the transcription factor 1-bet (encoded by Tbx21) was essential for the development of NKp46(+) ILCs but not of LTi cells or nuocytes. Deficiency in interleukin 22 (IL-22)-producing NKp46(+) ILCs resulted in greater susceptibility of Tbx21(-/-) mice to intestinal infection. Haploinsufficient 1-bet expression resulted in lower expression of the signaling molecule Notch, and Notch signaling was necessary for the transition of LTi cells into NKp46(+) ILCs. Furthermore, NKp46(+) ILCs differentiated solely from the CD4(-) LTi population, not the CD4(+) LTi population. Our results pinpoint the regulation of Notch signaling by 1-bet as a distinct molecular pathway that guides the development of NKp46(+) ILCs.