UC Irvine

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.