Aging restricts maturation of CXCL13+ T follicular helper cells in human immunity

Summary A decline in specific antibody responses is a hallmark of human aging, yet the differential contributions of B and T lymphocytes remain unclear. CXCL13 is a chemokine that shapes germinal center (GC) organization, but the regulation of human-specific CXCL13⁺ T follicular helper (Tfh) cells during aging is not known. Using human tonsil organoids, single-cell RNA sequencing, and CRISPR perturbations, we mapped age-associated changes in Tfh cells, the cell type that provides help to B cells in GCs. Tonsil organoids from older donors generate weaker influenza-specific antibody responses, which we trace to Tfh cell defects rather than B cells. Single-cell profiling revealed a selective loss of mature CXCL13⁺ GC-Tfh cells accompanied by accumulation of precursor states. Trajectory analysis shows that aging arrests Tfh maturation at the early activated precursor transition, and CRISPR perturbations identify BACH2 and SOX4 as regulators of differentiation reduced with age. These findings reveal a human-specific mechanism of immune aging with implications for strategies to restore humoral immunity.