BATF is an essential regulator of migratory ILC2 cell fate and function

Abstract

Abstract A recently identified subset of group-2 innate lymphoid cells (ILC2s) migrates to mucosal tissues early during type-2 inflammation and is characterized by responsiveness to interleukin-25 and high expression of KLRG1. This study identifies the major transcriptional regulator required for their generation and function. RNA-sequencing and unbiased pathway analysis revealed the AP-1 transcription factor BATF as a potential modulator of ILC2 cell fate. Indeed, infection of BATF-deficient mice with the helminth N. brasiliensis showed a selective defect in IL-25-induced, ILC2-mediated worm clearance as well as a corresponding loss of IL17RB+ (IL-25 receptor) KLRG1high ILC2s in the lung. Moreover, these BATF-dependent migratory ILC2s serve as the major early source of IL-4 and IL-13 after infection. Interestingly, while the presence of KLRG1high ILC2s in the small intestine are unaffected by BATF-deficiency, their ability to produce IL-13 is significantly impacted. Defects in IL-13 expression by intestinal KLRG1high ILC2s corresponded with decreased goblet and tuft cell hyperplasia in BATF-deficient mice, supporting the critical role of these migratory ILC2s as early sentinels of mucosal barrier integrity.