Group 3 innate lymphoid cells continuously require the transcription factor GATA-3 after commitment

Abstract

Abstract We have previously reported that the transcription factor GATA-3 is critical for the development of all interleukin 7 receptor α-chain (IL-7Rα)-expressing innate lymphoid cells (ILCs) from their progenitor. After ILC lineage commitment, GATA-3 is essential for the maintenance and function of group 2 ILCs (ILC2 cells). Moreover, GATA-3 also maintains low expression in other mature ILCs, such as ILC3 cells, but its function is still elusive. We found that GATA-3 regulated the homeostasis of ILC3 cells by controlling IL-7Rα expression. In addition, GATA-3 served an indispensable function for the further development of the NKp46+ ILC3 subset. GATA-3 bound directly to the Rorc locus in ILC3 cells, repressed RORγt expression, and, thus, regulated the balance between the transcription factors T-bet and RORγt during NKp46+ ILC3 development. Whole transcriptome comparison of CCR6+ lymphoid tissue-inducer (LTi) ILC3 and NKp46+ ILC3 subsets from Gata3 sufficient and deficient mice showed that, among NKp46+ ILC3 cells, GATA-3 not only positively regulated genes specific to the NKp46+ ILC3 subset, but also negatively regulated genes specific to LTi ILC3 cells. Furthermore, GATA-3 also bound to the Il22 promoter locus and was required for IL-22 production in both ILC3 subsets. Mice deficient for Gata3 in ILC3 cells succumbed to Citrobacter rodentium infection due to defective IL-22 production. In conclusion, despite its low expression, GATA-3 was required for the homeostasis, development and function of ILC3 subsets.