Upon activation, naive CD4⁺ T cells differentiate into distinct T cell subsets via processes reliant on epigenetically regulated, lineage-specific developmental programs. Here, we examined the function of the histone methyltransferase SETDB1 in T helper (Th) cell differentiation. Setdb1^−/− naive CD4⁺ T cells exhibited exacerbated Th1 priming, and when exposed to a Th1-instructive signal, Setdb1^−/− Th2 cells crossed lineage boundaries and acquired a Th1 phenotype. SETDB1 did not directly control Th1 gene promoter activity but relied instead on deposition of the repressive H3K9me3 mark at a restricted and cell-type-specific set of endogenous retroviruses (ERVs) located in the vicinity of genes involved in immune processes. Refined bioinformatic analyses suggest that these retrotransposons regulate Th1 gene cis-regulatory elements or act as Th1 gene enhancers. Thus, H3K9me3 deposition by SETDB1 ensures Th cell lineage integrity by repressing a repertoire of ERVs that have been exapted into cis-regulatory modules to shape and control the Th1 gene network.

激活后，幼稚的CD4 ⁺ T细胞通过依赖表观遗传调控的，谱系特异性的发育程序，分化为不同的T细胞亚群。在这里，我们检查了组蛋白甲基转移酶SETDB1在T辅助（Th）细胞分化中的功能。Setdb1 ^-/-幼稚的CD4 ⁺ T细胞表现出恶化的Th1引发，当暴露于Th1指导性信号时，Setdb1 ^-/-Th2细胞越过谱系边界并获得Th1表型。SETDB1不能直接控制Th1基因启动子的活性，而是依赖于抑制性H3K9me3标记在受限和特定细胞类型的内源性逆转录病毒（ERV）处的沉积，该内源性逆转录病毒位于参与免疫过程的基因附近。精细的生物信息学分析表明，这些逆转座子调节Th1基因的顺式调控元件或充当Th1基因的增强子。因此，SETDB1的H3K9me3沉积可通过抑制一系列ERV来确保Th细胞谱系完整性，这些ERV已被改编为顺式调控模块以塑造和控制Th1基因网络。