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

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^hiCXCR5^hiBcl6^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.

It is debated how follicular helper T (Tfh) cells versus central memory CD4⁺ T cells arise from similar precursors, and little is known about the regulation of germinal-centre (GC)-Tfh cell differentiation. Here, authors establish markers in the early precursor stage that distinguish between the GC-Tfh and memory T cell fates and identify an important mechanism that regulates the competitive fitness of the GC-Tfh cells.