Age-associated impairment of T cell immunity is linked to sex-dimorphic elevation of N-glycan branching.

Abstract

Impaired T cell immunity with aging increases mortality from infectious disease. The branching of Asparagine-linked glycans is a critical negative regulator of T cell immunity. Here we show that branching increases with age in females more than males, in naïve more than memory T cells, and in CD4⁺ more than CD8⁺ T cells. Female sex hormones and thymic output of naïve T cells (T_N) decrease with age, however neither thymectomy nor ovariectomy altered branching. Interleukin-7 (IL-7) signaling was increased in old female more than male mouse T_N cells, and triggered increased branching. N-acetylglucosamine, a rate-limiting metabolite for branching, increased with age in humans and synergized with IL-7 to raise branching. Reversing elevated branching rejuvenated T cell function and reduced severity of <i>Salmonella</i> infection in old female mice. These data suggest sex-dimorphic antagonistic pleiotropy, where IL-7 initially benefits immunity through T_N maintenance but inhibits T_N function by raising branching synergistically with age-dependent increases in N-acetylglucosamine.