Research ArticleT CELLS

Developmental bifurcation of human T follicular regulatory cells

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Science Immunology  28 May 2021:
Vol. 6, Issue 59, eabd8411
DOI: 10.1126/sciimmunol.abd8411

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Reconstructing TFR cell development

Antibody responses, including against self-antigens, are tightly controlled within germinal centers (GCs) by balancing the activity of T follicular regulatory (TFR) and helper (TFH) cells. Kumar et al. reconstructed the developmental trajectory of TFR cells using flow cytometry indexed single-cell transcriptomics of follicular T cells isolated from human peripheral blood, lymph nodes, and tonsils. After distinguishing TFR cells from other follicular T cell populations based on gene signature, they used transcriptomics to support a model in which mature GC TFR cells arise from regulatory T cells, with circulating TFR cells representing a separate developmental pathway. These results suggest that mature TFR cells primarily arise independently from their less mature counterpart in peripheral blood, providing further insight into how human TFR cells develop.


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 (TFH) and regulatory (TFR) cells is critical for adequate control of GC responses. The study of human TFH and TFR 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 TFH and TFR 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 TFH and TFR cells. We found that the dominant maturation of TFR cells follows a bifurcated trajectory from precursor Treg cells, with one arm of the bifurcation leading to blood TFR cells and the other leading to the most mature GC TFR cells. Overall, our data provide a comprehensive resource for the transcriptomics of different follicular T cell populations and their dynamic relationship across different tissues.

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