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-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.

TGF-β specifies T FH versus T H 17 cell fates in murine CD4 + T cells through c-Maf

“…CXCR5 hi PD-1 hi GC T FH cells were also almost absent in T cell–specific Maf Δ/Δ mice in chronic LCMV infection (fig. S8, C and D), further underscoring the in vivo relevance and complementing previous reports in other experimental models ( 44 , 45 , 49 , 50 ). Although spleen cellularity was similar, gut-draining mesenteric lymph nodes exhibited elevated total cell counts in infected Maf Δ/Δ mice (Fig.…”

Dysregulation of circulating T follicular helper cell subsets and their potential role in the pathogenesis of syphilis

“…Previously, CD45RO and CCR7 were used to define naïve and memory Tfh cells, which included CD45RO − CCR7 + naïve, CD45RO + CCR7 − effector memory, and CD45RO + CCR7 + central memory Tfh cells ( 21 , 22 ). The central memory CXCR5 + Tfh cells could support the antibody-mediated immune responses ( 23 ). Thus, we assessed these Tfh subsets in secondary syphilis and latent syphilis patients.…”