The divergence of PD-1+CXCR5+CD4+ T cell differentiation and stage-specific regulation of GC-Tfh cells

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Abstract T follicular helper (Tfh) cells were discovered as CD4+ T cells in the B cell follicles that express CXCR5 and help germinal center (GC) B cell responses. However, it is not clear which PD-1+CXCR5+Bcl6+CD4+ T cells will differentiate into PD-1hiCXCR5hiBcl6hiGC-Tfh cells while the others have a different fate, nor is it clear how GC-Tfh cell differentiation is regulated. Here we report that the sustained Tigit expression in PD-1+CXCR5+CD4+ T cells marked the precursor Tfh (pre-Tfh) to GC-Tfh transition, whereas Tigit−PD-1+CXCR5+CD4+ T cells upregulated IL-7Ra to become CXCR5+CD4+ T memory precursor/memory cells—with or without a CCR7+ (or CCR7+CD62L+) central memory phenotype. Our study further shows that pre-Tfh cells undergo substantial further differentiation at the transcriptome and chromatin accessibility levels to become GC-Tfh cells. Mechanistically, we find that c-Maf exerted an important function in the pre- to GC-Tfh transition, and we have identified c-Maf downstream factor Plekho1 as a novel regulator that played a stage-specific role in GC-Tfh cell differentiation.

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