Immunological function declines with age, increasing the susceptibility and severity of infections in the elderly. For example, those who are 65 years of age and older make up around 15% of the U.S. population but represents nearly 90% of the deaths associated with influenza. This age-associated reduction in immunity has been attributed to the dysfunction of both the innate and adaptive immune system. Indeed, functional capacity of T cells is severely diminished and is exacerbated with age. Our lab has revealed that N-linked glycans play a critical role in controlling T cell immunity in mice and humans. Furthermore, irregularity in N-glycosylation as a mechanism for dysfunction of T cells in the elderly has not been examined as of yet.

Here we report N-glycan branching in T cells increases with age in females, leading to T cell hypo-activity and increased susceptibility to infection. Reducing N-glycan branching rejuvenates T cell activation, proliferation and pro-inflammatory TH17 over anti-inflammatory Treg differentiation in aged female T cells. Susceptibility of aged female mice to Salmonella typhimurium invasion/dissemination was reduced by lowering N-glycan branching. A critical metabolic precursor of N-glycosylation and branching is N-acetylglucosamine (GlcNAc), a common amino sugar that is part of the regular human diet. GlcNAc is endogenous to human serum, increases with age and correlates with N-glycan branching in female > male human T cells. Interleukin-7 (IL-7) signaling synergistically regulates N-glycan branching with environmental GlcNAc. Both adoptive transfer of aged female T cells into young mice and negatively regulating IL-7 reversed aged-dependent increase in N-glycan branching. These results suggest that age-dependent increases of N-glycan branching, via increased supply of GlcNAc and IL-7 signaling, impairs T cell immunity in the elderly females, providing a novel mechanism to supplement current treatments for age-related diseases.