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

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, Emily R. Brown, Changchun Xiao, Olaf Kutsch, Yohsuke Harada, Matthew E. Pipkin and Hui Hu ()
Additional contact information
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

Nature Communications, 2023, vol. 14, issue 1, 1-15

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-39299-3

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