Circulating precursor CCR7^loPD-1^hi CXCR5⁺ CD4⁺ T cells indicate tfh cell activity and promote antibody responses upon antigen reexposure

Follicular B helper T (Tfh) cells support high affinity and long-term antibody responses. Here we found that within circulating CXCR5⁺ CD4⁺ Tcells in humans and mice, the CCR7^loPD-1^hi subset has a partial Tfh effector phenotype, whereas CCR7^hiPD-1^lo cells have a resting phenotype. The circulating CCR7^loPD-1^hi subset was indicative of active Tfh differentiation in lymphoid organs and correlated with clinical indices in autoimmune diseases. Thus the CCR7^loPD-1^hi subset provides a biomarker to monitor protective antibody responses during infection or vaccination and pathogenic antibody responses in autoimmune diseases. Differentiation of both CCR7^hiPD-1^lo and CCR7^loPD-1^hi subsets required ICOS and BCL6, but not SAP, suggesting that circulating CXCR5⁺ helper Tcells are primarily generated before germinal centers. Upon antigen reencounter, CCR7^loPD-1^hi CXCR5⁺ precursors rapidly differentiate into mature Tfh cells to promote antibody responses. Therefore, circulating CCR7^loPD-1^hi CXCR5⁺ CD4⁺ Tcells are generated during active Tfh differentiation and represent a new mechanism of immunological early memory.