Transcription Factor Bcl11b Controls Identity and Function of Mature Type 2 Innate Lymphoid Cells

• Bcl11b is expressed in mature ILC2s, but not in precursors
• Bcl11b maintains mILC2 genetic and functional programs through Gfi1, Gata3, and Rorα
• Bcl11b suppresses the ILC3 genetic program in ILC2s by repressing Rorc and Ahr
• Bcl11b−/− ILC2s expand in response to papain but cause ILC3-type airway inflammation

SummaryType 2 innate lymphoid cells (ILC2s) promote anti-helminth responses and contribute to allergies. Here, we report that Bcl11b, previously considered a T-cell-specific transcription factor, acted directly upstream of the key ILC2 transcription factor Gfi1 to maintain its expression in mature ILC2s. Consequently, Bcl11b−/− ILC2s downregulated Gata3 and downstream genes, including Il1rl1 (encoding IL-33 receptor), and upregulated Rorc and type 3 ILC (ILC3) genes. Additionally, independent of Gfi1, Bcl11b directly repressed expression of the gene encoding the ILC3 transcription factor Ahr, further contributing to silencing of ILC3 genes in ILC2s. Thus, Bcl11b−/− ILC2s lost their functions and gained ILC3 functions, and although they expanded in response to the protease allergen papain, they produced ILC3 but not ILC2 cytokines and caused increased airway infiltration of neutrophils instead of eosinophils. Our results demonstrate that Bcl11b is more than just a T-cell-only transcription factor and establish that Bcl11b sustains mature ILC2 genetic and functional programs and lineage fidelity.

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