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Elife ; 92020 12 15.
Article in English | MEDLINE | ID: covidwho-977809


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.

Aging/immunology , Autophagy/immunology , CD8-Positive T-Lymphocytes/immunology , Respiratory Syncytial Virus Vaccines/immunology , Spermidine/pharmacology , Adjuvants, Immunologic/pharmacology , Adult , Aged , Animals , Basic Helix-Loop-Helix Leucine Zipper Transcription Factors/metabolism , Cell Line, Tumor , Humans , Immunologic Memory/immunology , Interferon-gamma/blood , Jurkat Cells , Mice , Mice, Inbred C57BL , Mice, Knockout , Middle Aged , Peptide Initiation Factors/metabolism , RNA-Binding Proteins/metabolism , Respiratory Syncytial Viruses/immunology , Spermidine/blood , Vaccination , Young Adult