The heterogeneity and plasticity of T lymphocytes is critical for determining immune response outcomes. Functional regulatory T (Treg) cells are commonly characterized by stable FOXP3 expression and have reported to exhibit heterogeneous phenotypes under inflammatory conditions. However, the interplay between inflammation and Treg cell suppressive activity still remains elusive. Here, we utilized single-cell RNA sequencing to investigate how human Treg cells respond to the pro-inflammatory cytokine interleukin-6 (IL-6). We observed that Treg cells divided into two subpopulations after IL-6 stimulation. TIGIT⁻ unstable Treg cells lost FOXP3 expression and gained an effector-like T cell phenotype, whereas TIGIT⁺ Treg cells retained robust suppressive function. Single cell transcriptome analysis revealed a spectrum of cellular states of IL-6-stimulated Treg cells and how cytochrome P450 family 1 subfamily A member 1 (CYP1A1) is a crucial regulator of Treg cell suppressive capability and stability. CYP1A1-deficient human Treg cells developed a Th17-like phenotype after IL-6 stimulation. Our findings implicate CYP1A1 as a previously unidentified regulator of Treg cells that may have target potential for clinical application for biotherapies.

T 淋巴细胞的异质性和可塑性对于确定免疫反应结果至关重要。功能性调节性 T (Treg) 细胞通常以稳定的 FOXP3 表达为特征，并且据报道在炎症条件下表现出异质表型。然而，炎症和 Treg 细胞抑制活性之间的相互作用仍然难以捉摸。在这里，我们利用单细胞 RNA 测序来研究人类 Treg 细胞如何响应促炎细胞因子白细胞介素 6 (IL-6)。我们观察到 Treg 细胞在 IL-6 刺激后分为两个亚群。TIGIT ^-不稳定的 Treg 细胞失去 FOXP3 表达并获得效应样 T 细胞表型，而 TIGIT ⁺Treg 细胞保留了强大的抑制功能。单细胞转录组分析揭示了 IL-6 刺激的 Treg 细胞的一系列细胞状态，以及细胞色素 P450 家族 1 亚家族 A 成员 1 (CYP1A1) 如何成为 Treg 细胞抑制能力和稳定性的关键调节因子。CYP1A1 缺陷型人 Treg 细胞在 IL-6 刺激后出现 Th17 样表型。我们的研究结果表明 CYP1A1 是一种先前未被识别的 Treg 细胞调节剂，可能具有生物疗法临床应用的靶标潜力。