Autophagy in T cells from aged donors is maintained by spermidine and correlates with function and vaccine responses

Abstract

Vaccines are powerful tools to develop immune memory to infectious diseases and prevent excess mortality. In older adults, however vaccines are generally less efficacious and the molecular mechanisms that underpin this remain largely unknown. Autophagy, a process known to prevent aging, is critical for the maintenance of immune memory in mice. Here, we show that autophagy is specifically induced in vaccine-induced antigen-specific CD8+ T cells in healthy human volunteers. In addition, reduced IFNγ secretion by RSV-induced T cells in older vaccinees correlates with low autophagy levels. We demonstrate that levels of the endogenous autophagy-inducing metabolite spermidine fall in human T cells with age. Spermidine supplementation in T cells from old donors recovers their autophagy level and function, similar to young donors’ cells, in which spermidine biosynthesis has been inhibited. Finally, our data show that endogenous spermidine maintains autophagy via the translation factor eIF5A and transcription factor TFEB. In summary, we have provided evidence for the importance of autophagy in vaccine immunogenicity in older humans and uncovered two novel drug targets that may increase vaccination efficiency in the aging context.

The Role of T Cell Senescence in Neurological Diseases and Its Regulation by Cellular Metabolism

“…This supports the notion that alterations of metabolic pathways in immune cells may directly cause inflammation-induced neurodegeneration. Importantly, there is a multitude of potential approaches to counteract ageassociated immune cell malfunctions by metabolic intervention, including supplementation of age-limited nutrients such as formate and glycine, and reinforcement of autophagy with spermidine (47,62). Of note, a recent study reported that mTOR inhibitor therapy in elderly humans decreased the incidence of infections, improved influenza vaccination responses and up-regulated antiviral immunity (68), thus highlighting the potential clinical relevance of such metabolic approaches in age-related immune dysfunctions.…”

“…Recently, it was shown that spermidine modulates T cell differentiation towards a regulatory phenotype and dietary supplementation with spermidine reduced pathology in a mouse model of T cell transfer-induced colitis (61). Moreover, in a study in humans, spermidine supplementation was able to recover the autophagic flux and cellular functionality in T cells from old donors (62). Interestingly, spermidine was reported to reverse cellular senescence of B cells (63), an effect that has not yet been addressed in T cells.…”

Considerations for a Respiratory Syncytial Virus Vaccine Targeting an Elderly Population

“…By removing accumulated proteins and other unnecessary cytoplasmic material, autophagy limits cellular stress and promotes survival of long-lived memory cells [35,36]. Autophagy functions have been shown to decline with age [37,38]. Studies have shown that impairment of key autophagy genes in aged mice or by a genetic deletion system in young adult mice leads to loss of function in memory CD8 T cells and enhanced production of inflammatory cytokines including interferon (IFN)-γ, interleukin (IL)-1β, tumor necrosis factor (TNF), and IL-6 [38][39][40][41][42].…”

“…Autophagy functions have been shown to decline with age [37,38]. Studies have shown that impairment of key autophagy genes in aged mice or by a genetic deletion system in young adult mice leads to loss of function in memory CD8 T cells and enhanced production of inflammatory cytokines including interferon (IFN)-γ, interleukin (IL)-1β, tumor necrosis factor (TNF), and IL-6 [38][39][40][41][42]. Thus, impaired autophagy mechanisms in elderly individuals likely contribute to the inflammaging phenotype.…”

“…Thus, impaired autophagy mechanisms in elderly individuals likely contribute to the inflammaging phenotype. A recent study demonstrated that supplementation with the metabolite spermidine enhanced the function of T cells isolated from elderly adults by increasing autophagy level and function [38]. This suggests that designing an RSV vaccine that can restore autophagy functions may be an effective strategy for providing protection in an aged population.…”