The ETS 1 transcription factor is required for the development and cytokine-induced expansion of ILC 2

The Rockefeller University Press $30.00 J. Exp. Med. 2016 Vol. 213 No. 5 687–696 www.jem. org/cgi/doi/10.1084/jem.20150851 687 Group 2 innate lymphoid cells (ILC2s) are a subset of ILCs that reside at mucosal surfaces and contribute to immune response against extracellular pathogens, such as helminthes. These cells are present at a low frequency in the lungs of WT mice, but they expand substantially in response to IL-33 and IL-25, which are produced by damaged epithelial cells. ILC2s contribute to pathogen clearance by producing multiple cytokines, including IL-5 and IL-13, which recruit and activate eosinophils and neutrophils as well as amphiregulin, which contributes to the maintenance of the epithelium (McKenzie et al., 2014). Although involved in pathogen clearance, aberrant activation of ILC2s in the lungs leads to eosinophilia and airway inflammation, a hallmark of allergic asthma (McKenzie et al., 2014). Despite the critical role that these cells play in immunity and disease, the key mechanisms controlling ILC2 development and function are just beginning to be revealed. ILC2s are a subset of ILCs that share properties with T helper type 2 (Th2) cells. In adult mice, ILC2s develop in the BM from a common helper innate lymphoid progenitor (CHI LP), which arises from common lymphoid progenitors (CLPs) but has lost adaptive lymphoid (B and T lymphocyte) and NK cell potential (Verykokakis et al., 2014). All of the helper-like ILCs share a requirement for the transcription factors GATA3 and TCF1 and for the E protein transcription factor inhibitor ID2 (Moro et al., 2010; Satoh-Takayama et al., 2010; Yagi et al., 2014; Yang et al., 2015). Downstream of CHI LPs, ILC2 differentiation depends on the transcription factors ROR-α, GFI1, and BCL11b (Wong et al., 2012; Spooner et al., 2013; Califano et al., 2015; Walker et al., 2015; Yu et al., 2015). GFI1 promotes ILC2 development by maintaining GATA3, and it represses the expression of the ILC3 cytokine IL-17 (Spooner et al., 2013). BCL11b enforces the expression of GFI1 and similarly controls the development and functional properties of ILC2s (Califano et al., 2015). We previously demonstrated that the ETS1 transcription factor regulates Id2 transcription in NK cells (Pereira de Sousa et al., 2012; Ramirez et al., 2012). However, it is not known whether ETS1 plays a role in the transcriptional network that controls the emergence or activation of ILCs. Indeed, there have been few studies of ETS1 function in any cell type because of the high rate of neonatal lethality in mice carrying a germline deletion of Ets1 (Gao et al., 2010). Here, we report on a novel mouse model for the conditional deletion of ETS1. We demonstrate that BM CHI LPs could develop in the absence of ETS1 but are compromised in their fitness and their ability to generate ILC2s. ETS1 functions, at least in part, to promote the up-regulation of Id2 mRNA that is observed in ILC2s. We also identified a role for ETS1 in the cytokine-induced expansion of lung ILC2s and for their production of IL-5 and IL-13. Our data place ETS1 as a very early regulator in the transcriptional network controlling the emergence and function of ILC2s. Group 2 innate lymphoid cells (ILC2s) are a subset of ILCs that play a protective role in the response to helminth infection, but they also contribute to allergic lung inflammation. Here, we report that the deletion of the ETS1 transcription factor in lymphoid cells resulted in a loss of ILC2s in the bone marrow and lymph nodes and that ETS1 promotes the fitness of the common progenitor of all ILCs. ETS1-deficient ILC2 progenitors failed to up-regulate messenger RNA for the E protein transcription factor inhibitor ID2, a critical factor for ILCs, and these cells were unable to expand in cytokine-driven in vitro cultures. In vivo, ETS1 was required for the IL-33–induced accumulation of lung ILC2s and for the production of the T helper type 2 cytokines IL-5 and IL-13. IL-25 also failed to elicit an expansion of inflammatory ILC2s when these cells lacked ETS1. Our data reveal ETS1 as a critical regulator of ILC2 expansion and cytokine production and implicate ETS1 in the regulation of Id2 at the inception of ILC2 development. The ETS1 transcription factor is required for the development and cytokine-induced expansion of ILC2