The mechanisms by which FOXP3 + T follicular regulatory (Tfr) cells simultaneously steer antibody formation toward microbe or vaccine recognition and away from self-reactivity remain incompletely understood. To explore underappreciated heterogeneity in human Tfr cell development, function, and localization, we used paired TCRVA / TCRVB sequencing to distinguish tonsillar Tfr cells that are clonally related to natural regulatory T cells (nTfr) from those likely induced from T follicular helper (Tfh) cells (iTfr). The proteins iTfr and nTfr cells differentially expressed were used to pinpoint their in situ locations via multiplex microscopy and establish their divergent functional roles. In silico analyses and in vitro tonsil organoid tracking models corroborated the existence of separate T reg -to-nTfr and Tfh-to-iTfr developmental trajectories. Our results identify human iTfr cells as a distinct CD38 + , germinal center–resident, Tfh-descended subset that gains suppressive function while retaining the capacity to help B cells, whereas CD38 − nTfr cells are elite suppressors primarily localized in follicular mantles. Interventions differentially targeting specific Tfr cell subsets may provide therapeutic opportunities to boost immunity or more precisely treat autoimmune diseases.

中文翻译：

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人类 T 滤泡辅助克隆在生发中心-驻留调节库中播种

FOXP3 的机制+滤泡调节 T (Tfr) 细胞同时引导抗体形成朝向微生物或疫苗识别并远离自身反应仍不完全清楚。为了探索人类 Tfr 细胞发育、功能和定位中未被充分认识的异质性，我们使用了配对TCCRVA/TCCRVB测序以区分与自然调节性 T 细胞 (nTfr) 克隆相关的扁桃体 Tfr 细胞和可能由滤泡辅助 T (Tfh) 细胞 (iTfr) 诱导的扁桃体 Tfr 细胞。iTfr 和 nTfr 细胞差异表达的蛋白质用于通过多重显微镜精确定位它们的原位位置，并确定它们不同的功能作用。计算机分析和体外扁桃体类器官追踪模型证实了独立 T 的存在注册-to-nTfr 和 Tfh-to-iTfr 发育轨迹。我们的结果将人类 iTfr 细胞鉴定为独特的 CD38+，生发中心驻留，Tfh 后代子集获得抑制功能，同时保留帮助 B 细胞的能力，而 CD38-nTfr 细胞是主要位于滤泡套的精英抑制细胞。针对特定 Tfr 细胞亚群的差异性干预措施可能会提供增强免疫力或更精确地治疗自身免疫性疾病的治疗机会。