In response to various types of infection, naïve CD4 + T cells differentiate into diverse helper T cell subsets; however, the epigenetic programs that regulate differentiation in response to viral infection remain poorly understood. Demethylation of CpG dinucleotides by Tet methylcytosine dioxygenases is a key component of epigenetic programing that promotes specific gene expression, cellular differentiation, and function. We report that following viral infection, Tet2-deficient CD4 + T cells preferentially differentiate into highly functional germinal center T follicular helper (T FH ) cells that provide enhanced help for B cells. Using genome-wide DNA methylation and transcription factor binding analyses, we find that Tet2 coordinates with multiple transcription factors, including Foxo1 and Runx1, to mediate the demethylation and expression of target genes, including genes encoding repressors of T FH differentiation. Our findings establish Tet2 as an important regulator of T FH cell differentiation and reveal pathways that could be targeted to enhance immune responses against infectious disease.

中文翻译：

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Tet2 与 Foxo1 和 Runx1 协调以平衡 T 滤泡辅助细胞和 T 辅助 1 细胞分化

为了应对各种类型的感染，幼稚 CD4+T 细胞分化成不同的辅助性 T 细胞亚群；然而，调节病毒感染反应分化的表观遗传程序仍然知之甚少。Tet 甲基胞嘧啶双加氧酶对 CpG 二核苷酸的去甲基化是促进特定基因表达、细胞分化和功能的表观遗传编程的关键组成部分。我们报告说，在病毒感染后，Tet2 缺陷型 CD4+T 细胞优先分化为功能强大的生发中心 T 滤泡辅助细胞 (T跳频) 为 B 细胞提供增强帮助的细胞。使用全基因组 DNA 甲基化和转录因子结合分析，我们发现 Tet2 与多个转录因子协调，包括 Foxo1 和 Runx1，以介导目标基因的去甲基化和表达，包括编码 T 抑制因子的基因跳频分化。我们的研究结果将 Tet2 确立为 T 的重要调节因子跳频细胞分化并揭示可靶向增强针对传染病的免疫反应的途径。