Regulatory T cells (Tregs) exert inhibitory function under various physiological conditions and adopt diverse characteristics following environmental cues. Multiple subsets of Tregs expressing master transcription factors of helper T cells such as RORγt, T-bet, Gata3 and PPARγ have been characterized, but the molecular mechanism governing the differentiation of these subsets remains largely unknown. Here we report that the atypical IκB protein family member Bcl-3 suppresses RORγt⁺ Treg accumulation. The suppressive effect of Bcl-3 was particularly evident in the mouse immune tolerance model of anti-CD3 therapy. Using conditional knockout mice, we illustrate that loss of Bcl-3 specifically in Tregs was sufficient to boost RORγt⁺ Treg formation and resistance of mice to dextran sulfate sodium-induced colitis. We further demonstrate the suppressive effect of Bcl-3 on RORγt⁺ Treg differentiation in vitro. Our results reveal a novel role of nuclear factor-kappa B signaling pathways in Treg subset differentiation that may have clinical implications in immunotherapy.

中文翻译：

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Bcl-3 抑制 RORγt+ 调节性 T 细胞的分化

调节性 T 细胞 (Tregs) 在各种生理条件下发挥抑制功能，并根据环境线索采取不同的特征。表达辅助性 T 细胞主转录因子的 Tregs 的多个亚群如 RORγt、T-bet、Gata3 和 PPARγ 已被表征，但控制这些亚群分化的分子机制仍然很大程度上未知。在这里，我们报告非典型 IκB 蛋白家族成员 Bcl-3 抑制 RORγt ⁺ Treg 积累。Bcl-3的抑制作用在抗CD3治疗的小鼠免疫耐受模型中尤为明显。使用条件性敲除小鼠，我们说明在 Tregs 中特异性 Bcl-3 的丢失足以增强 RORγt ⁺Treg的形成和小鼠对葡聚糖硫酸钠诱导的结肠炎的抵抗力。我们进一步证明了 Bcl-3 在体外对 RORγt ⁺ Treg 分化的抑制作用。我们的研究结果揭示了核因子-kappa B 信号通路在 Treg 亚群分化中的新作用，这可能在免疫治疗中具有临床意义。