Autophagy in T cells from aged donors is maintained by spermidine, and correlates with function and vaccine responses
- University of Oxford, United Kingdom
- University College London, United Kingdom
- Université de Strasbourg, France
- University of Birmingham, United Kingdom
Abstract
Older adults are at high risk for infectious diseases such as observed at the recent COVID-19 outbreak and vaccination seems to be the only long-term solution to the pandemic. While most vaccines are less efficacious in older adults, little is known about the molecular mechanisms that underpin this. Autophagy, a major degradation pathway and one of the few processes 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 IFN secretion by RSV-induced T cells in older vaccinees correlates with low autophagy levels. We demonstrate in human donors that levels of the endogenous autophagy-inducing metabolite spermidine fall in T cells with age. Spermidine supplementation of 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. With these findings we have uncovered novel targets and biomarkers for the development of anti-aging drugs for human T cells, providing evidence for the use of spermidine in improving vaccine immunogenicity in the aged human population.
Data availability
All data generated or analysed during this study are included in the manuscript and supporting files. Source data files have been provided for Figures 1-5 and figure supplements.
Article and author information
Author details
Funding
Wellcome (WT109665MA)
- Anna Katharina Simon
National Institute for Health Research
- Paul Klenerman
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: Animal experiments were approved by the local ethical review committee and performed under UK project licenses PPL 30/3388.
Human subjects: Human vaccine samples: Human peripheral blood mononuclear cells (PBMC) were obtained under the ethics reference NRES Berkshire 13/SC/0023, from phase I clinical trials of novel viral-vectored vaccines for hepatitis-C virus (HCV; NCT01070407 and NCT01296451)or respiratory syncytial virus (RSV).Human healthy control: The study was approved by the Local Ethics Committee Oxford and Birmingham:The acquisition of normal control human tissue for medical research Kennedy Institute of Rheumatology. University of Oxford, Rec: 11/h0711/7 collection.University of Birmingham Research Ethics Committee, Reference ERN_12-1184R2 , Investigations of the ageing immune system" Application for Ethical Review ERN_12-1184R2, UoB Ref: 17-1106.
Copyright
© 2020, Alsaleh et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Autophagy in T cells from aged donors is maintained by spermidine, and correlates with function and vaccine responses
eLife 9:e57950.
https://doi.org/10.7554/eLife.57950
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