BATF acts as an essential regulator of IL-25–responsive migratory ILC2 cell fate and function

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Science Immunology  10 Jan 2020:
Vol. 5, Issue 43, eaay3994
DOI: 10.1126/sciimmunol.aay3994

Early epithelial responder

Innate lymphoid cell 2 (ILC2) cells can be defined as two distinct cell subsets based on responsiveness to IL-25 (called iILC2) or IL-33 (called nILC2). Miller et al. identified the AP-1 superfamily transcription factor BATF as a modulator of ILC2 fate. BATF-deficient mice infected with Nippostrongylus brasiliensis lacked iILC2 cells, were unable to protect against infection, and displayed defective ILC2-cytokine responses. Further investigation revealed that IL-25–responsive BATF-dependent migratory iILC2 expressed low levels of arginase-1, making them distinct from tissue-resident nILC2. BATF-dependent iILC2 cells also produced IL-4 and IL-13 during helminth infection in the lung and intestine. These findings indicate that these BATF-dependent migratory iILC2s can respond early to epithelial damage and contribute to the restoration of the epithelium.


A transitory, interleukin-25 (IL-25)–responsive, group 2 innate lymphoid cell (ILC2) subset induced during type 2 inflammation was recently identified as iILC2s. This study focuses on understanding the significance of this population in relation to tissue-resident nILC2s in the lung and intestine. RNA-sequencing and pathway analysis revealed the AP-1 superfamily transcription factor BATF (basic leucine zipper transcription factor, activating transcription factor–like) as a potential modulator of ILC2 cell fate. Infection of BATF-deficient mice with Nippostrongylus brasiliensis showed a selective defect in IL-25–mediated helminth clearance and a corresponding loss of iILC2s in the lung characterized as IL-17RBhigh, KLRG1high, BATFhigh, and Arg1low. BATF deficiency selectively impaired iILC2s because it had no impact on tissue-resident nILC2 frequency or function. Pulmonary-associated iILC2s migrated to the lung after infection, where they represented an early source of IL-4 and IL-13. Although the composition of ILC2s in the small intestine was distinct from those in the lung, their frequency and IL-13 expression remained dependent on BATF, which was also required for optimal goblet and tuft cell hyperplasia. Findings support IL-25–responsive ILC2s as early sentinels of mucosal barrier integrity.

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