Department of Biochemistry and Molecular Genetics, The Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
Department of Dermatology, The Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
Nature. 2024 Jul;631(8022):857-866. doi: 10.1038/s41586-024-07627-2. Epub 2024 Jul 10.
Systemic lupus erythematosus (SLE) is prototypical autoimmune disease driven by pathological T cell-B cell interactions. Expansion of T follicular helper (T) and T peripheral helper (T) cells, two T cell populations that provide help to B cells, is a prominent feature of SLE. Human T and T cells characteristically produce high levels of the B cell chemoattractant CXCL13 (refs. ), yet regulation of T cell CXCL13 production and the relationship between CXCL13 T cells and other T cell states remains unclear. Here, we identify an imbalance in CD4 T cell phenotypes in patients with SLE, with expansion of PD-1/ICOS CXCL13 T cells and reduction of CD96 IL-22 T cells. Using CRISPR screens, we identify the aryl hydrocarbon receptor (AHR) as a potent negative regulator of CXCL13 production by human CD4 T cells. Transcriptomic, epigenetic and functional studies demonstrate that AHR coordinates with AP-1 family member JUN to prevent CXCL13 T/T cell differentiation and promote an IL-22 phenotype. Type I interferon, a pathogenic driver of SLE, opposes AHR and JUN to promote T cell production of CXCL13. These results place CXCL13 T/T cells on a polarization axis opposite from T helper 22 (T22) cells and reveal AHR, JUN and interferon as key regulators of these divergent T cell states.
系统性红斑狼疮 (SLE) 是一种由病理性 T 细胞- B 细胞相互作用驱动的典型自身免疫性疾病。滤泡辅助性 T 细胞 (Tfh) 和外周辅助性 T 细胞 (Tpt) 的扩增，这两种向 B 细胞提供帮助的 T 细胞群体，是 SLE 的一个显著特征。人类 T 和 T 细胞通常会产生高水平的 B 细胞趋化因子 CXCL13（参考文献），但 T 细胞 CXCL13 产生的调节以及 CXCL13 T 细胞与其他 T 细胞状态之间的关系仍不清楚。在这里，我们在 SLE 患者中鉴定出 CD4 T 细胞表型的不平衡，表现为 PD-1/ICOS CXCL13 T 细胞的扩增和 CD96 IL-22 T 细胞的减少。使用 CRISPR 筛选，我们鉴定出芳香烃受体 (AHR) 是人类 CD4 T 细胞中 CXCL13 产生的强有力的负调节剂。转录组学、表观遗传学和功能研究表明，AHR 与 AP-1 家族成员 JUN 协调，以防止 CXCL13 T/T 细胞分化并促进 IL-22 表型。SLE 的致病驱动因素 I 型干扰素，拮抗 AHR 和 JUN 以促进 T 细胞产生 CXCL13。这些结果将 CXCL13 T/T 细胞置于与辅助性 22 细胞（T22）相反的极化轴上，并揭示 AHR、JUN 和干扰素作为这些不同 T 细胞状态的关键调节剂。
