The development of pathogenic autoreactive CD4+ T cells, particularly in the context of impaired signaling, remains poorly understood. Unraveling how defective signaling pathways contribute to their activation and persistence is crucial for identifying new therapeutic targets. We profiled a highly arthritogenic subset of naïve CD4+ T cells using bulk and single-cell RNA and TCR sequencing from SKG mice, which develop CD4+ T cell mediated autoimmune arthritis driven by a hypomorphic mutation in Zap70-a key TCR signaling kinase. Despite impaired signaling, these cells exhibit heightened expression of T cell activation and cytokine signaling genes, but diminished expression of a subset of tolerogenic markers (Izumo1r, Tnfrsf9, Cd5, S100a11) compared to wild-type cells. The arthritogenic cells show an enrichment for TCR variable beta (Vβ) chains targeting superantigens from the endogenous mouse mammary tumor virus (MMTV) but exhibit diminished induction of tolerogenic markers following peripheral antigen encounter, contrasting with the robust induction of negative regulators seen in wild-type cells. In arthritic joints, cells expressing superantigen-reactive Vβs expand alongside detectable MMTV proviruses. Antiretroviral treatment and superantigen-reactive T cell depletion curtail SKG arthritis, suggesting that endogenous retroviruses disrupt peripheral tolerance and promote the activation and differentiation of self-reactive CD4+ T cells into pathogenic effector cells.

中文翻译：

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内源性抗原在自身免疫性关节炎模型中塑造转录组和 TCR 库。


致病性自身反应性 CD4+ T 细胞的发育，尤其是在信号传导受损的情况下，仍然知之甚少。揭示有缺陷的信号通路如何导致其激活和持续存在，对于确定新的治疗靶点至关重要。我们使用来自 SKG 小鼠的大量和单细胞 RNA 和 TCR 测序分析了高度致关节炎的幼稚 CD4+ T 细胞亚群，这些小鼠发展为 CD4+ T 细胞介导的自身免疫性关节炎，由 Zap70-a 关键 TCR 信号激酶的亚型突变驱动。尽管信号传导受损，但与野生型细胞相比，这些细胞表现出 T 细胞活化和细胞因子信号转导基因的表达升高，但致耐受性标志物子集 （Izumo1r、Tnfrsf9、Cd5、S100a11） 的表达降低。致关节炎细胞显示靶向内源性小鼠乳腺肿瘤病毒 （MMTV） 超抗原的 TCR 可变 β （Vβ） 链富集，但在遇到外周抗原后表现出致耐受性标志物的诱导减少，这与野生型细胞中观察到的负调节因子的强烈诱导形成鲜明对比。在关节炎关节中，表达超抗原反应性 Vβ 的细胞与可检测到的 MMTV 前病毒一起扩增。抗逆转录病毒治疗和超抗原反应性 T 细胞耗竭可抑制 SKG 关节炎，表明内源性逆转录病毒破坏外周耐受性并促进自身反应性 CD4+ T 细胞激活和分化为致病性效应细胞。