Innate lymphoid cell precursors (ILCPs) develop into distinct subsets of innate lymphoid cells (ILCs) with specific functions. The epigenetic program underlying the differentiation of ILCPs into ILC subsets remains poorly understood. Here, we reveal the genome-wide distribution and dynamics of the DNA methylation and hydroxymethylation in ILC subsets and their respective precursors. Additionally, we find that the DNA hydroxymethyltransferase TET1 suppresses ILC1 but not ILC2 or ILC3 differentiation. TET1 deficiency promotes ILC1 differentiation by inhibiting TGF-β signaling. Throughout ILCP differentiation at postnatal stage, gut microbiota contributes to the downregulation of TET1 level. Microbiota decreases the level of cholic acid in the gut, impairs TET1 expression and suppresses DNA hydroxymethylation, ultimately resulting in an expansion of ILC1s. In adult mice, TET1 suppresses the hyperactivation of ILC1s to maintain intestinal homeostasis. Our findings provide insights into the microbiota-mediated epigenetic programming of ILCs, which links microbiota-DNA methylation crosstalk to ILC differentiation.

先天淋巴样细胞前体 (ILCP) 发育成具有特定功能的先天淋巴样细胞 (ILC) 的不同亚群。 ILCP 分化为 ILC 亚群的表观遗传程序仍知之甚少。在这里，我们揭示了 ILC 亚群及其各自前体中 DNA 甲基化和羟甲基化的全基因组分布和动态。此外，我们发现 DNA 羟甲基转移酶 TET1 抑制 ILC1，但不抑制 ILC2 或 ILC3 分化。 TET1 缺陷通过抑制 TGF-β 信号传导促进 ILC1 分化。在出生后阶段的整个 ILCP 分化过程中，肠道微生物群有助于 TET1 水平的下调。微生物群降低肠道内胆酸水平，损害 TET1 表达并抑制 DNA 羟甲基化，最终导致 ILC1 扩增。在成年小鼠中，TET1 抑制 ILC1 的过度激活以维持肠道稳态。我们的研究结果提供了对微生物介导的 ILC 表观遗传编程的见解，该编程将微生物群-DNA 甲基化串扰与 ILC 分化联系起来。