Stepwise differentiation of follicular helper T cells reveals distinct developmental and functional states

Manuel A. Podestà, Cecilia B. Cavazzoni, Benjamin L. Hanson, Elsa D. Bechu, Garyfallia Ralli, Rachel L. Clement, Hengcheng Zhang, Pragya Chandrakar, Jeong-Mi Lee, Tamara Reyes-Robles, Reza Abdi, Alos Diallo, Debattama R. Sen and Peter T. Sage ()
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Manuel A. Podestà: Harvard Medical School
Cecilia B. Cavazzoni: Harvard Medical School
Benjamin L. Hanson: Harvard Medical School
Elsa D. Bechu: Harvard Medical School
Garyfallia Ralli: Harvard Medical School
Rachel L. Clement: Harvard Medical School
Hengcheng Zhang: Harvard Medical School
Pragya Chandrakar: Harvard Medical School
Jeong-Mi Lee: Harvard Medical School
Tamara Reyes-Robles: Merck & Co., Inc.
Reza Abdi: Harvard Medical School
Alos Diallo: Harvard Medical School
Debattama R. Sen: Harvard Medical School
Peter T. Sage: Harvard Medical School

Nature Communications, 2023, vol. 14, issue 1, 1-17

Abstract: Abstract Follicular helper T (Tfh) cells are essential for the formation of high affinity antibodies after vaccination or infection. Although the signals responsible for initiating Tfh differentiation from naïve T cells have been studied, the signals controlling sequential developmental stages culminating in optimal effector function are not well understood. Here we use fate mapping strategies for the cytokine IL-21 to uncover sequential developmental stages of Tfh differentiation including a progenitor-like stage, a fully developed effector stage and a post-effector Tfh stage that maintains transcriptional and epigenetic features without IL-21 production. We find that progression through these stages are controlled intrinsically by the transcription factor FoxP1 and extrinsically by follicular regulatory T cells. Through selective deletion of Tfh stages, we show that these cells control antibody dynamics during distinct stages of the germinal center reaction in response to a SARS-CoV-2 vaccine. Together, these studies demonstrate the sequential phases of Tfh development and how they promote humoral immunity.

Date: 2023
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DOI: 10.1038/s41467-023-43427-4

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