Journal
NATURE IMMUNOLOGY
Volume 22, Issue 10, Pages 1245-+Publisher
NATURE PORTFOLIO
DOI: 10.1038/s41590-021-01024-x
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Fiancette et al. used inducible transcription factor deletion models in mature tissue-resident ILCs to uncover complementary and competing transcriptional networks determining ILC3 phenotype and functional capacity. The study demonstrated the importance of ROR gamma t and ROR alpha in maintaining optimal effector functions in ILC3s, with ROR alpha being sufficient for robust interleukin-22 production in LTi-like ILC3 subset but not in NCR(+) ILC3s. Further, continued ROR gamma t expression was essential to restrain type 1 immunity associated transcriptional networks in NCR+ ILC3s coexpressing T-bet.
Fiancette et al. utilize models of inducible transcription factor deletion in mature tissue-resident ILCs to reveal complementary and competing transcriptional networks that determine ILC3 phenotype and functional capacity. Innate lymphoid cells (ILCs) are guardians of mucosal immunity, yet the transcriptional networks that support their function remain poorly understood. We used inducible combinatorial deletion of key transcription factors (TFs) required for ILC development (ROR gamma t, ROR alpha and T-bet) to determine their necessity in maintaining ILC3 identity and function. Both ROR gamma t and ROR alpha were required to preserve optimum effector functions; however, ROR alpha was sufficient to support robust interleukin-22 production among the lymphoid tissue inducer (LTi)-like ILC3 subset, but not natural cytotoxicity receptor (NCR)(+) ILC3s. Lymphoid tissue inducer-like ILC3s persisted with only selective loss of phenotype and effector functions even after the loss of both TFs. In contrast, continued ROR gamma t expression was essential to restrain transcriptional networks associated with type 1 immunity within NCR+ ILC3s, which coexpress T-bet. Full differentiation to an ILC1-like population required the additional loss of ROR alpha. Together, these data demonstrate how TF networks integrate within mature ILCs after development to sustain effector functions, imprint phenotype and restrict alternative differentiation programs.
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