Defective TFH Cell Function and Increased TFR Cells Contribute to Defective Antibody Production in Aging

• Stimulatory TFH and inhibitory TFR cells expand with age, with higher TFR:TFH ratios
• TFH cells from aged mice show defects in antigen-specific B cell help
• Aged and young TFR cells have equal suppressive capacity
• Impaired TFH and increased TFR cells result in diminished B cell responses in aging

SummaryDefective antibody production in aging is broadly attributed to immunosenescence. However, the precise immunological mechanisms remain unclear. Here, we demonstrate an increase in the ratio of inhibitory T follicular regulatory (TFR) cells to stimulatory T follicular helper (TFH) cells in aged mice. Aged TFH and TFR cells are phenotypically distinct from those in young mice, exhibiting increased programmed cell death protein-1 expression but decreased ICOS expression. Aged TFH cells exhibit defective antigen-specific responses, and programmed cell death protein-ligand 1 blockade can partially rescue TFH cell function. In contrast, young and aged TFR cells have similar suppressive capacity on a per-cell basis in vitro and in vivo. Together, these studies reveal mechanisms contributing to defective humoral immunity in aging: an increase in suppressive TFR cells combined with impaired function of aged TFH cells results in reduced T-cell-dependent antibody responses in aged mice.

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