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

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 in males, in naive T cells (TN) more than in memory T cells, and in CD4+ more than in CD8+ T cells. Female sex hormones and thymic output of TN cells decrease with age; however, neither thymectomy nor ovariectomy altered branching. Interleukin-7 (IL-7) signaling was increased in old female more than male mouse TN 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 Salmonella infection in old female mice. These data suggest sex-dimorphic antagonistic pleiotropy, where IL-7 initially benefits immunity through TN maintenance but inhibits TN function by raising branching synergistically with age-dependent increases in N-acetylglucosamine.