1. Computational and Systems Biology
  2. Immunology and Inflammation

Memory CD4 T cell subsets are kinetically heterogeneous and replenished from naive T cells at high levels

  1. Graeme Gossel
  2. Thea Hogan
  3. Daniel Cownden
  4. Benedict Seddon  Is a corresponding author
  5. Andrew J Yates  Is a corresponding author
  1. Hunter College, City University of New York, United States
  2. University College London, United Kingdom
  3. University of Glasgow, United Kingdom
https://doi.org/10.7554/eLife.23013
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  1. Graeme Gossel
  2. Thea Hogan
  3. Daniel Cownden
  4. Benedict Seddon
  5. Andrew J Yates
(2017)
Memory CD4 T cell subsets are kinetically heterogeneous and replenished from naive T cells at high levels
eLife 6:e23013.
https://doi.org/10.7554/eLife.23013
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Abstract

Characterising the longevity of immunological memory requires establishing the rules underlying the renewal and death of peripheral T cells. However, we lack knowledge of the population structure and how self-renewal and de novo influx contribute to maintenance of memory compartments. Here, we characterise the kinetics and structure of murine CD4 T cell memory subsets by measuring the rates of influx of new cells and using detailed timecourses of DNA labelling that also distinguish the behaviour of recently divided and quiescent cells. We find that both effector and central memory CD4 T cells comprise subpopulations with highly divergent rates of turnover, and show that inflows of new cells sourced from the naive pool strongly impact estimates of memory cell lifetimes and division rates. We also demonstrate that the maintenance of CD4 T cell memory subsets in healthy mice is unexpectedly and strikingly reliant on this replenishment.

Article and author information

Author details

  1. Graeme Gossel

    Department of Physics and Astronomy, Hunter College, City University of New York, New York, United States
    Competing interests
    The authors declare that no competing interests exist.

  2. Thea Hogan

    Institute of Immunity and Transplantation, University College London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.

  3. Daniel Cownden

    Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.

  4. Benedict Seddon

    Institute of Immunity and Transplantation, University College London, London, United Kingdom
    For correspondence
    benedict.seddon@ucl.ac.uk
    Competing interests
    The authors declare that no competing interests exist.

  5. Andrew J Yates

    Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, United Kingdom
    For correspondence
    andrew.yates@glasgow.ac.uk
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-4606-4483

Funding

National Institutes of Health (R01 AI093870)

  • Andrew J Yates

Arthritis Research UK

  • Andrew J Yates

Medical Research Council (MC-PC-13055)

  • Thea Hogan
  • Benedict Seddon

National Science Foundation (1548123)

  • Graeme Gossel

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: All experiments were performed in accordance with UK Home Office regulations, project license number PPL70-8310.

Reviewing Editor

  1. Rob de Boer, University of Utrecht, Netherlands

Publication history

  1. Received: November 5, 2016
  2. Accepted: March 4, 2017
  3. Accepted Manuscript published: March 10, 2017 (version 1)
  4. Version of Record published: May 11, 2017 (version 2)
  5. Version of Record updated: February 8, 2018 (version 3)

Copyright

© 2017, Gossel 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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  1. Graeme Gossel
  2. Thea Hogan
  3. Daniel Cownden
  4. Benedict Seddon
  5. Andrew J Yates
(2017)
Memory CD4 T cell subsets are kinetically heterogeneous and replenished from naive T cells at high levels
eLife 6:e23013.
https://doi.org/10.7554/eLife.23013

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Further reading

    1. Immunology and Inflammation

    Differential impact of self and environmental antigens on the ontogeny and maintenance of CD4+ T cell memory

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    Laboratory mice develop populations of circulating memory CD4+ T cells in the absence of overt infection. We have previously shown that these populations are replenished from naive precursors at high levels throughout life (Gossel et al., 2017). However, the nature, relative importance and timing of the forces generating these cells remain unclear. Here, we tracked the generation of memory CD4+ T cell subsets in mice housed in facilities differing in their ‘dirtiness’. We found evidence for sequential naive to central memory to effector memory development, and confirmed that both memory subsets are heterogeneous in their rates of turnover. We also inferred that early exposure to self and environmental antigens establishes persistent memory populations at levels determined largely, although not exclusively, by the dirtiness of the environment. After the first few weeks of life, however, these populations are continuously supplemented by new memory cells at rates that are independent of environment.

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    T-cell Immunology: The maths of memory

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    Mathematical modeling reveals that long-term immunological memory is maintained in a manner that is even more dynamic than previously thought.

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