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.
Highlights
The outbreak of coronavirus disease 2019 (COVID-19) caused a great threat to global public health in 2020 with the majority of deaths occurring in older adults
We used in vitro stimulated control peripheral blood mononuclear cells (PBMCs) obtained from five young donors (22–50 years old), bled on three different occasions, 2 weeks apart, were stimulated with either IFNg/LPS, anti-CD40 /-IgM or anti-CD3/CD28 to induce autophagy in monocytes (Figure 1—figure supplement 2a), B cells
Data represented as mean ± SEM. (e, f) Correlation of autophagic flux with total response to peptide pools specific T cell IFNg response to respiratory syncytial virus (RSV) exposure measured by ELISpot in CD8+ cells from old donors (e) and young donors (f), donors as in (d)
Summary
The outbreak of coronavirus disease 2019 (COVID-19) caused a great threat to global public health in 2020 with the majority of deaths occurring in older adults. We uncovered a novel pathway in which spermidine donates a residue for the hypusination of the translation factor eIF5a, which is necessary for the translation of a three proline motif present in the master transcription factor of autophagy and lysosomal biogenesis, called TFEB (Zhang et al, 2019). We demonstrated that this pathway operates in activated B cells, which upon activation have an unusually high-protein synthesis rate, owing to the high production of immunoglobulins. This work highlights the potential of spermidine as a vaccine adjuvant in the older adults
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