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 A. 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, Hui Hu
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-1 hi CXCR5 hi Bcl6 hi 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.