Circulating precursor CCR7loPD-1hi CXCR5+ CD4+ T cells indicate Tfh cell activity and promote antibody responses upon antigen reexposure

Abstract

Follicular B helper T (Tfh) cells support high affinity and long-term antibody responses. Here we found that within circulating CXCR5+ CD4+ T cells in humans and mice, the CCR7loPD-1hi subset has a partial Tfh effector phenotype, whereas CCR7hiPD-1lo cells have a resting phenotype. The circulating CCR7loPD-1hi subset was indicative of active Tfh differentiation in lymphoid organs and correlated with clinical indices in autoimmune diseases. Thus the CCR7loPD-1hi subset provides a biomarker to monitor protective antibody responses during infection or vaccination and pathogenic antibody responses in autoimmune diseases. Differentiation of both CCR7hiPD-1lo and CCR7loPD-1hi subsets required ICOS and BCL6, but not SAP, suggesting that circulating CXCR5+ helper T cells are primarily generated before germinal centers. Upon antigen reencounter, CCR7loPD-1hi CXCR5+ precursors rapidly differentiate into mature Tfh cells to promote antibody responses. Therefore, circulating CCR7loPD-1hi CXCR5+ CD4+ T cells are generated during active Tfh differentiation and represent a new mechanism of immunological early memory.