Germinal centers (GCs) are anatomic structures where B cells undergo affinity maturation, leading to production of high-affinity antibodies. The balance between T follicular helper (T_FH) and regulatory (T_FR) cells is critical for adequate control of GC responses. The study of human T_FH and T_FR cell development has been hampered because of the lack of in vitro assays reproducing in vivo biology, along with difficult access to healthy human lymphoid tissues. We used a single-cell transcriptomics approach to study the maturation of T_FH and T_FR cells isolated from human blood, iliac lymph nodes (LNs), and tonsils. As independent tissues have distinct proportions of follicular T cells in different maturation states, we leveraged the heterogeneity to reconstruct the maturation trajectory for human T_FH and T_FR cells. We found that the dominant maturation of T_FR cells follows a bifurcated trajectory from precursor T_reg cells, with one arm of the bifurcation leading to blood T_FR cells and the other leading to the most mature GC T_FR cells. Overall, our data provide a comprehensive resource for the transcriptomics of different follicular T cell populations and their dynamic relationship across different tissues.

生发中心 (GC) 是 B 细胞经历亲和力成熟的解剖结构，从而产生高亲和力抗体。_{T 滤泡辅助细胞 (T FH} ) 和调节 (T _FR ) 细胞之间的平衡对于充分控制 GC 反应至关重要。由于缺乏复制体内生物学的体外试验，以及难以获得健康的人体淋巴组织，人类 T _FH和 T _{FR细胞发育的研究受到了阻碍。}我们使用单细胞转录组学方法来研究 T _FH和 T _FR的成熟从人体血液、髂淋巴结 (LN) 和扁桃体中分离出的细胞。由于独立组织在不同成熟状态下具有不同比例的滤泡 T 细胞，我们利用异质性重建人类 T _FH和 T _FR细胞的成熟轨迹。我们发现 T _FR细胞的主要成熟遵循前体 T _reg细胞的分叉轨迹，分叉的一个臂导致血液 T _FR细胞，另一臂导致最成熟的 GC T _FR细胞。总体而言，我们的数据为不同滤泡 T 细胞群的转录组学及其在不同组织之间的动态关系提供了全面的资源。