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

Abstract

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.

The Heterogeneity, Origins, and Impact of Migratory iILC2 Cells in Anti-helminth Immunity

“…After N. brasiliensis infection, there was a statistically significant increase in non-fate mapped pulmonary ILC2s indicating that ILC2s do not arise solely from self-renewal during inflammation but may be recruited to the lung from other sites (135,136). This is supported by studies where the appearance of iILC2s in the lung depends on S1P-dependent migration (120,136,144,145). In these studies, administration of the S1P-receptor agonist FTY720 prevented the appearance of iILC2s in the lung after IL-25 administration or helminth infection, indicating the requirement for iILC2s to egress from lymphoid organs into circulation.…”

“…As their functional determinants imply, iILC2s which preferentially respond to IL-25 express more IL-25 receptor, whereas IL-33-responsive nILC2s display more IL-33 receptor on their surface (118,120). Together, these markers allowed the consistent delineation between iILC2 and nILC2 cells (Figure 2).…”

“…Regarding experiments to assess conversion, it should be noted that while delineation of iILC2 and nILC2 populations based on KLRG1 expression works well for N. brasiliensis infection, there are other situations which lead nILC2s to increase KLRG1 levels. In particular, daily IL-33-administration for 4 days, as well as repopulation of irradiated mice with bone marrow, leads nILC2s to upregulate KLRG1 levels and drop CD90 slightly so that their phenotype resembles an intermediate between nILC2s and iILC2s (120). Moreover, these changes may be strain-and context-specific as Alternaria alternata exposure or IL-33 administration over 2 weeks lead to upregulation of CD90 on ILC2s isolated from bronchoalveolar lavage fluid in C57BL/6 but not BALB/c mice (140).…”

“…This mechanism would be consistent with the idea that pulmonary iILC2 cells originating in the intestine lose their nILC2 phenotype prior to their arrival in the lung. We previously proposed that such a conversion from an nILC2 phenotype toward an iILC2 phenotype must occur if pulmonary iILC2s originate in the intestine based on the uniform expression of the nILC2 marker arginase-1 within intestinal ILC2 cells and its absence among pulmonary iILC2 cells (120). However, because pulmonary and mesenteric iILC2 populations have not been directly compared, care should be taken in overinterpreting these conclusions at least as they relate to an intestinal origin for pulmonary iILC2 populations.…”

“…First, addition of IL-25 and not IL-33 drives the appearance of pulmonary iILC2 cells suggesting that IL-33 may differentially impact mesenteric iILC2 and pulmonary iILC2 (118,147). Second, while ST2 expression is abundant on nILC2 cells residing in the lung, few intestinal nILC2 cells express the IL-33 receptor at steady state (except in conditions where IL-33 expression in the intestine is forced by a transgene) (120,147). How IL-33 is modulating intestinal ILC2s or whether specific ST2 + subsets are responsible for the generation of mesenteric iILC2s will be of interest.…”