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

A decline in specific antibody responses is a hallmark of human aging, yet the differential contributions of B and T lymphocytes and their interactions remain unclear. CXCL13 is a critical chemokine that shapes germinal center organization, but the regulation of human-specific CXCL13+ Tfh cells during aging is not known. Using human tonsil organoids, single-cell RNA sequencing, and CRISPR perturbations, we mapped age-associated changes in T follicular helper (Tfh) cells, the cell type that provides T cell "help" to B cells in germinal centers (GCs). Tonsil organoids from older donors generated weaker influenza-specific antibody responses, which we traced 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 Tfh precursor states. Trajectory analysis showed that aging arrests Tfh cell maturation at the early activated precursor transition, and CRISPR perturbations identified BACH2 and SOX4 as transcriptional regulators of differentiation reduced with age. These findings reveal a human-specific mechanism of immune aging with implications for strategies to restore humoral immunity.