1. Immunology and Inflammation
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Autophagy in T cells from aged donors is maintained by spermidine, and correlates with function and vaccine responses

  1. Ghada Alsaleh  Is a corresponding author
  2. Isabel Panse
  3. Leo Swadling
  4. Hanlin Zhang
  5. Felix Richter
  6. Alain Meyer
  7. Janet Lord
  8. Eleanor Barnes
  9. Paul Klenerman
  10. Christopher Green
  11. Anna Katharina Simon  Is a corresponding author
  1. University of Oxford, United Kingdom
  2. University College London, United Kingdom
  3. Université de Strasbourg, France
  4. University of Birmingham, United Kingdom
Research Article
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Cite this article as: eLife 2020;9:e57950 doi: 10.7554/eLife.57950

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

  1. Ghada Alsaleh

    The Kennedy Institute of Rheumatology, NDORMS, University of Oxford, Oxford, United Kingdom
    For correspondence
    ghada.alsaleh@kennedy.ox.ac.uk
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-4211-3420
  2. Isabel Panse

    The Kennedy Institute of Rheumatology, NDORMS, University of Oxford, OXford, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  3. Leo Swadling

    Division of Infection and Immunity, University College London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  4. Hanlin Zhang

    The Kennedy Institute of Rheumatology, NDORMS, University of Oxford, Oxford, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  5. Felix Richter

    The Kennedy Institute of Rheumatology, NDORMS, University of Oxford, Oxford, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  6. Alain Meyer

    Fédération de médecine translationnelle, Université de Strasbourg, Strasbourg, France
    Competing interests
    The authors declare that no competing interests exist.
  7. Janet Lord

    MRC-Versus Arthritis Centre for Musculoskeletal Ageing Research, Institute of Inflammation and Ageing,, University of Birmingham, Birmingham, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  8. Eleanor Barnes

    Peter Medawar Building for Pathogen Research, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  9. Paul Klenerman

    Nuffield Dept of Medicine, University of Oxford, Oxford, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-4307-9161
  10. Christopher Green

    Oxford Vaccine Group, Department of Paediatrics, University of Oxford, Oxford, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  11. Anna Katharina Simon

    The Kennedy Institute of Rheumatology, NDORMS, University of Oxford, Oxford, United Kingdom
    For correspondence
    katja.simon@kennedy.ox.ac.uk
    Competing interests
    The authors declare that no competing interests exist.

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.

Reviewing Editor

  1. David Furman, Buck Institute For Research On Aging

Publication history

  1. Received: April 16, 2020
  2. Accepted: November 30, 2020
  3. Accepted Manuscript published: December 15, 2020 (version 1)
  4. Version of Record published: December 16, 2020 (version 2)

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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