Transforming growth factor-ß and Notch ligands act as opposing environmental cues in the plasticity of type 3 innate lymphoid cells

Group 3 innate lymphoid cells (ILC3) are composed of NCR- and NCR+ subsets located at mucosal sites exposed to billions of commensal microbes and potentially harmful pathogens. Together with T cells, the various ILC3 subsets maintain the balance between homeostasis and immune activation. Using genetic mapping, we reveal here the existence of a new subset of NCR- ILC3 transiently expressing Ncr1 but strongly related to unlabeled NCR- ILC3, demonstrating previously unsuspected heterogeneity within the NCR- ILC3 population. Notch signaling is required for the differentiation of NCR- ILC3 into NCR+ ILC3. However, we show here that Notch signaling must be sustained for the maintenance of the NCR+ phenotype and that TGF-ß impairs the development of NCR+ ILC3. Thus, ILC3 diversity and the plasticity of the NCR- and NCR+ subsets is regulated by the balance between the opposing effects of Notch and TGF-ß signaling, maintaining homeostasis in the face of continual challenges. Overall design: Transcriptional profiling of three ILC subsets (NCR-FM-, NCR-FM- and NCR+FM+) using RNA sequencing

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Viant C, Rankin LC, Girard-Madoux MJ, Seillet C, Shi W, Smyth MJ, Bartholin L, Walzer T, Huntington ND, Vivier E, Belz GT