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

Abstract

Type 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. Regulation of mature innate lymphoid cell identity and function is poorly understood. Avram and colleagues demonstrate that Bcl11b, a transcription factor previously considered specific to T cells, sustains key ILC2 transcription factors and restricts essential ILC3 transcription factors in mature ILC2s, thus maintaining the genetic and functional programs of peripheral ILC2s.