Laboratory of Molecular Immunology, National Institutes of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
Immunol Cell Biol. 2021 Jul;99(6):586-595. doi: 10.1111/imcb.12441. Epub 2021 Feb 23.
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.
调节性 T 细胞（Tregs）在各种生理条件下发挥抑制功能，并根据环境线索采用不同的特征。已经鉴定出多种表达辅助性 T 细胞主转录因子（如 RORγt、T-bet、Gata3 和 PPARγ）的 Treg 亚群，但控制这些亚群分化的分子机制在很大程度上仍不清楚。本文报道了非典型 IκB 蛋白家族成员 Bcl-3 抑制 RORγt Treg 的积累。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。通过条件性敲除小鼠，我们说明 Treg 中 Bcl-3 的缺失足以促进 RORγt Treg 的形成，并提高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。我们的结果揭示了核因子-κB 信号通路在 Treg 亚群分化中的新作用，这可能对免疫治疗具有临床意义。
