<br>RPA1 缺失会损害外周 T 细胞稳态，并通过触发 T 细胞坏死性凋亡而加剧炎症损伤,Advanced Science

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RPA1 缺失会损害外周 T 细胞稳态，并通过触发 T 细胞坏死性凋亡而加剧炎症损伤
Advanced Science ( IF 14.3 ) Pub Date : 2023-01-31 , DOI: 10.1002/advs.202206344
Jia Song ₁ , Xin Zhang ₂ , Yue Yin ₂ , Mengfan Guo ₂ , Xuyang Zhao ₂ , Likun Wang ₂ , Caixia Ren ₃ , Yuxin Yin ₂ , Xuehui Zhang ₁ , Xuliang Deng ₁ , Dan Lu ₂

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通过胸腺输出的微调和初始 T 细胞的自我更新，外周 T 细胞库保持动态稳态。淋巴细胞减少或淋巴细胞数量减少与自身免疫性疾病有关，但人们对体内平衡机制知之甚少。据报道，复制蛋白 A1 (RPA1) 在 T 细胞稳态中发挥着关键作用。利用 T 细胞特异性Rpa1缺陷 ( Rpa1 ^fl/fl Cd4-cre ) 小鼠， Rpa1的缺失通过抑制外周 T 细胞群和限制 TCR 库多样性而导致淋巴细胞减少。此外， Rpa1 ^fl/fl Cd4-cre小鼠表现出对炎症性疾病（包括结肠炎和肝炎）的易感性增加。临床分析表明，溃疡性结肠炎或其他自身炎症性疾病患者中RPA1的表达降低。从机制上讲，RPA1 的消耗通过触发基因组 DNA 渗漏到细胞质中来激活 ZBP1-RIPK3 信号传导，从而导致 T 细胞坏死性凋亡。 RPA1 缺陷引起的这种坏死性 T 细胞死亡会导致损伤相关分子模式 (DAMP) 的释放，进而招募白细胞并加剧炎症反应。相反，对坏死性凋亡信号的化学或遗传抑制可以改善Rpa1缺陷引起的炎症损伤。因此，这些研究揭示了 RPA1-ZBP1-RIPK3 轴在 T 细胞稳态中的重要性，并为自身炎症性疾病的治疗提供了一种有前途的策略。

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Loss of RPA1 Impairs Peripheral T Cell Homeostasis and Exacerbates Inflammatory Damage through Triggering T Cell Necroptosis

The peripheral T cell pool is maintained at dynamic homeostasis through fine-tuning of thymic output and self-renewal of naïve T cells. Lymphopenia or reduced lymphocyte number is implicated in autoimmune diseases, yet little is known about the homeostatic mechanisms. Here, it is reported that the replication protein A1 (RPA1) plays a critical role in T cell homeostasis. Utilizing T cell-specific Rpa1-deficient (Rpa1^fl/fl Cd4-cre) mice, loss of Rpa1 results in lymphopenia through restraining peripheral T cell population and limiting TCR repertoire diversity. Moreover, Rpa1^fl/fl Cd4-cre mice exhibit increased susceptibility to inflammatory diseases, including colitis and hepatitis. Clinical analysis reveals that the expression of RPA1 is reduced in patients with ulcerative colitis or other autoinflammatory diseases. Mechanistically, depletion of RPA1 activates ZBP1-RIPK3 signaling through triggering the genomic DNA leakage into cytosol, consequently resulting in T cell necroptosis. This necroptotic T cell death induced by RPA1 deficiency allows the release of damage-associated molecular patterns (DAMPs), which in turn recruits leukocytes and exacerbates inflammatory response. Reciprocally, chemical or genetic inhibition of necroptosis signaling can ameliorate the Rpa1 deficiency-induced inflammatory damage. The studies thus uncover the importance of RPA1-ZBP1-RIPK3 axis in T cell homeostasis and provide a promising strategy for autoinflammatory disease treatment.

更新日期：2023-01-31

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