Data_Sheet_1_The NF-κB RelA Transcription Factor Is Critical for Regulatory T Cell Activation and Stability.docx

Regulatory T cells (Tregs) play a major role in immune homeostasis and in the prevention of autoimmune diseases. It has been shown that c-Rel is critical in Treg thymic differentiation, but little is known on the role of NF-κB on mature Treg biology. We thus generated mice with a specific knockout of RelA, a key member of NF-κB, in Tregs. These mice developed a severe autoimmune syndrome with multi-organ immune infiltration and high activation of lymphoid and myeloid cells. Phenotypic and transcriptomic analyses showed that RelA is critical in the acquisition of the effector Treg state independently of surrounding inflammatory environment. Unexpectedly, RelA-deficient Tregs also displayed reduced stability and cells that had lost Foxp3 produced inflammatory cytokines. Overall, we show that RelA is critical for Treg biology as it promotes both the generation of their effector phenotype and the maintenance of their identity.

调节性T细胞（Regulatory T cells, Tregs）在免疫稳态维持与自身免疫病防控中发挥核心作用。已有研究证实c-Rel对Treg的胸腺分化至关重要，但目前学界对核因子κB（NF-κB）在成熟Treg生物学功能中的作用仍知之甚少。为此，我们构建了在Treg中特异性敲除NF-κB关键亚基RelA的小鼠模型。该模型小鼠出现严重自身免疫综合征，表现为多器官免疫浸润以及淋巴样细胞与髓样细胞的高度活化。表型与转录组分析显示，RelA可独立于周围炎症环境，对效应性Treg状态的建立发挥关键调控作用。出乎意料的是，RelA缺陷的Treg还表现出稳定性下降，且丢失Foxp3的细胞会分泌促炎细胞因子。综上，本研究证实RelA对Treg生物学功能至关重要，其可同时促进效应性Treg表型的形成与细胞身份的维持。