Group 2 innate lymphoid cells (ILC2s) manifest tissue heterogeneity and are crucial modulators of regional immune responses. The molecular mechanisms regulating tissue ILC2 properties remain elusive. Here, we interrogate the signatures of ILC2s from five tissues at the transcriptome and epigenetic level. We have found that tissue microenvironment strongly shapes ILC2 identities. The intestine induces Aiolos+ILC2s, whereas lung and pancreas enhance Galectin-1+ILC2s. Though being a faithful gut ILC2 feature under the steady state, Aiolos is induced in non-intestinal ILC2s by pro-inflammatory cytokines. Specifically, IL-33 stimulates Aiolos expression in both human and mouse non-intestinal ILC2s. Functionally, Aiolos facilitates eosinophil recruitment by supporting IL-5 production and proliferation of ST2+ILC2s through inhibiting PD-1. At the epigenetic level, ILC2 tissue characters are imprinted by open chromatin regions (OCRs) at non-promoters. Intestinal-specific transcription factor aryl hydrocarbon receptor (Ahr) binds to Ikzf3 (encoding Aiolos) locus, increases the accessibility of an intestinal ILC2-specific OCR, and promotes the Ikzf3 transcription by enhancing H3K27ac. Consequently, Ahr prevents ILC2s entering an “exhausted-like” state through sustaining Aiolos expression. Our work elucidates mechanism of ILC2 tissue adaptation and highlights Aiolos as a potential target of type 2 inflammation.

Treg cells acquire distinct transcriptional properties to suppress specific inflammatory responses. Transcription characteristics of Treg cells are regulated by epigenetic modifications, the mechanism of which remains obscure. Here, we report that Setd2, a histone H3K36 methyltransferase, is important for the survival and suppressive function of Treg cells, especially those from the intestine. Setd2 supports GATA3+ST2+ intestinal thymic-derived Treg (tTreg) cells by facilitating the expression and reciprocal relationship of GATA3 and ST2 in tTreg cells. IL-33 preferentially boosts Th2 cells rather than GATA3+ Treg cells in Foxp3Cre-YFPSetd2 flox/flox mice, corroborating the constraint of Th2 responses by Setd2 expression in Treg cells. SETD2 sustains GATA3 expression in human Treg cells, and SETD2 expression is increased in Treg cells from human colorectal cancer tissues. Epigenetically, Setd2 regulates the transcription of target genes (including Il1rl1) by modulating the activity of promoters and intragenic enhancers where H3K36me3 is typically deposited. Our findings provide mechanistic insights into the regulation of Treg cells and intestinal immunity by Setd2.