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Spatiotemporal resolution of germinal center Tfh cell differentiation and divergence from central memory CD4+ T cell fate

Author

Listed:
  • Fangming Zhu

    (University of Alabama at Birmingham)

  • Ryan J. McMonigle

    (University of Alabama at Birmingham)

  • Andrew R. Schroeder

    (University of Alabama at Birmingham)

  • Xianyou Xia

    (University of Alabama at Birmingham)

  • David Figge

    (University of Alabama at Birmingham)

  • Braxton D. Greer

    (University of Alabama at Birmingham)

  • Edahí González-Avalos

    (La Jolla Institute for Immunology)

  • Diego O. Sialer

    (University of Alabama at Birmingham)

  • Yin-Hu Wang

    (University of Alabama at Birmingham)

  • Kelly M. Chandler

    (University of Alabama at Birmingham)

  • Adam J. Getzler

    (The Scripps Research Institute)

  • Emily R. Brown

    (University of Alabama at Birmingham)

  • Changchun Xiao

    (The Scripps Research Institute)

  • Olaf Kutsch

    (University of Alabama at Birmingham)

  • Yohsuke Harada

    (University of Science)

  • Matthew E. Pipkin

    (The Scripps Research Institute)

  • Hui Hu

    (University of Alabama at Birmingham)

Abstract

Follicular helper T (Tfh) cells are essential for germinal center (GC) B cell responses. However, it is not clear which PD-1+CXCR5+Bcl6+CD4+ T cells will differentiate into PD-1hiCXCR5hiBcl6hi GC-Tfh cells and how GC-Tfh cell differentiation is regulated. Here, we report that the sustained Tigit expression in PD-1+CXCR5+CD4+ T cells marks the precursor Tfh (pre-Tfh) to GC-Tfh transition, whereas Tigit–PD-1+CXCR5+CD4+ T cells upregulate IL-7Rα to become CXCR5+CD4+ T memory cells with or without CCR7. We demonstrate that pre-Tfh cells undergo substantial further differentiation at the transcriptome and chromatin accessibility levels to become GC-Tfh cells. The transcription factor c-Maf appears critical in governing the pre-Tfh to GC-Tfh transition, and we identify Plekho1 as a stage-specific downstream factor regulating the GC-Tfh competitive fitness. In summary, our work identifies an important marker and regulatory mechanism of PD-1+CXCR5+CD4+ T cells during their developmental choice between memory T cell fate and GC-Tfh cell differentiation.

Suggested Citation

  • Fangming Zhu & Ryan J. McMonigle & Andrew R. Schroeder & Xianyou Xia & David Figge & Braxton D. Greer & Edahí González-Avalos & Diego O. Sialer & Yin-Hu Wang & Kelly M. Chandler & Adam J. Getzler & Em, 2023. "Spatiotemporal resolution of germinal center Tfh cell differentiation and divergence from central memory CD4+ T cell fate," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-39299-3
    DOI: 10.1038/s41467-023-39299-3
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    References listed on IDEAS

    as
    1. Hai Qi & Jennifer L. Cannons & Frederick Klauschen & Pamela L. Schwartzberg & Ronald N. Germain, 2008. "SAP-controlled T–B cell interactions underlie germinal centre formation," Nature, Nature, vol. 455(7214), pages 764-769, October.
    2. Xindong Liu & Xin Chen & Bo Zhong & Aibo Wang & Xiaohu Wang & Fuliang Chu & Roza I. Nurieva & Xiaowei Yan & Ping Chen & Laurens G. van der Flier & Hiroko Nakatsukasa & Sattva S. Neelapu & Wanjun Chen , 2014. "Transcription factor achaete-scute homologue 2 initiates follicular T-helper-cell development," Nature, Nature, vol. 507(7493), pages 513-518, March.
    3. Heping Xu & Xuanying Li & Dan Liu & Jianfu Li & Xu Zhang & Xin Chen & Shiyue Hou & Lixia Peng & Chenguang Xu & Wanli Liu & Lianfeng Zhang & Hai Qi, 2013. "Follicular T-helper cell recruitment governed by bystander B cells and ICOS-driven motility," Nature, Nature, vol. 496(7446), pages 523-527, April.
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