Self-reactive T cells experience chronic antigen exposure but do not exhibit signs of exhaustion. Here, we investigated the mechanisms for sustained, functioning autoimmune CD4+ T cells despite chronic stimulation. Examination of T cell priming showed that CD4+ T cells activated in the absence of infectious signals retained TCF1 expression. At later time points and during blockade of new T cell recruitment, most islet-infiltrating autoimmune CD4+ T cells were TCF1+, although expression was reduced on a per T cell basis. The Tcf7 locus was epigenetically modified in circulating autoimmune CD4+ T cells, suggesting a pre-programmed de novo methylation of the locus in early stages of autoimmune CD4+ T cell differentiation. This mirrored the epigenetic profile of recently recruited CD4+CD62L+ T cells in the pancreas. Collectively, these data reveal a unique environment during autoimmune CD4+ T cell priming that allows T cells to fine-tune TCF1 expression and maintain long-term survival and function.

中文翻译：

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自身免疫性 CD4+ T 细胞微调 TCF1 表达，以维持功能并在糖尿病期间持续抗原暴露后存活


自身反应性 T 细胞会经历慢性抗原暴露，但没有表现出疲惫的迹象。在这里，我们研究了在慢性刺激下仍能维持、功能正常的自身免疫性 CD4+ T 细胞的机制。T 细胞启动检查表明，在没有感染信号的情况下激活的 CD4 + T 细胞保留了 TCF1 表达。在较晚的时间点和阻断新 T 细胞募集期间，大多数胰岛浸润性自身免疫性 CD4+ T 细胞是 TCF1 + ，尽管每个 T 细胞的表达降低。Tcf7 基因座在循环自身免疫性 CD4+ T 细胞中进行了表观遗传修饰，表明在自身免疫性 CD4+ T 细胞分化的早期阶段，该基因座存在预编程的从头甲基化。这反映了胰腺中最近募集的 CD4+CD62L+ T 细胞的表观遗传学特征。总的来说，这些数据揭示了自身免疫性 CD4+ T 细胞启动过程中的独特环境，使 T 细胞能够微调 TCF1 表达并维持长期存活和功能。