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

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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 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.
Funding Information
  • U.S. Department of Health & Human Services | NIH | National Institute of Allergy and Infectious Diseases (R01AI126277, R01AI114625, R01AI108917, R01AI144403)
  • U.S. Department of Health & Human Services | NIH | National Center for Complementary and Integrative Health (R01AT007452)

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