Aging is a significant risk factor for autoimmunity, and many autoimmune diseases tend to onset during adulthood. We conducted an extensive analysis of CD4⁺ T cell subsets from 354 patients with autoimmune disease and healthy controls via flow cytometry and bulk RNA sequencing. As a result, we identified a distinct CXCR3^midCD4⁺ effector memory T cell subset that expands with age, which we designated “age-associated T helper (T_HA) cells.” T_HA cells exhibited both a cytotoxic phenotype and B cell helper functions, and these features were regulated by the transcription factor ZEB2. Consistent with the highly skewed T cell receptor usage of T_HA cells, gene expression in T_HA cells from patients with systemic lupus erythematosus reflected disease activity and was affected by treatment with a calcineurin inhibitor. Moreover, analysis of single-cell RNA sequencing data revealed that T_HA cells infiltrate damaged organs in patients with autoimmune diseases. Together, our characterization of T_HA cells may facilitate improved understanding of the relationship between aging and autoimmune diseases.

中文翻译：

---

自身免疫中具有 B 细胞促进功能的年龄相关 CD4+ T 细胞受 ZEB2 调节

衰老是自身免疫的一个重要危险因素，许多自身免疫性疾病往往在成年期发病。我们通过流式细胞术和批量 RNA 测序对 354 名自身免疫性疾病患者和健康对照者的 CD4 ⁺ T 细胞亚群进行了广泛分析。结果，我们发现了一种独特的 CXCR3^中CD4 ⁺效应记忆 T 细胞亚群，该亚群随着年龄的增长而扩展，我们将其命名为“年龄相关 T 辅助细胞 (TH _A ) 细胞”。 T _H A 细胞同时表现出细胞毒性表型和 B 细胞辅助功能，并且这些特征受到转录因子 ZEB2 的调节。与 T _H A细胞的高度倾斜的 T H A 细胞受体使用一致，系统性红斑狼疮患者的T _H A 细胞中的基因表达反映了疾病活动性，并受到钙调神经磷酸酶抑制剂治疗的影响。此外，对单细胞RNA测序数据的分析表明，TH _A细胞浸润自身免疫性疾病患者受损的器官。总之，我们对 T _H A 细胞的表征可能有助于加深对衰老与自身免疫性疾病之间关系的理解。