Developmental bifurcation of human T follicular regulatory cells

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.