Modulation of let-7 miRNAs controls the differentiation of effector CD8 T cells

  1. Alexandria C Wells
  2. Keith A Daniels
  3. Constance C Angelou
  4. Eric Fagerberg
  5. Amy S Burnside
  6. Michele Markstein
  7. Dominique Alfandari
  8. Raymond M Welsh
  9. Elena L Pobezinskaya  Is a corresponding author
  10. Leonid A Pobezinsky  Is a corresponding author
  1. University of Massachusetts, United States
  2. University of Massachusetts Medical School, United States

Abstract

The differentiation of naïve CD8 T cells into effector cytotoxic T lymphocytes upon antigen stimulation is necessary for successful anti-viral, and anti-tumor immune responses. Here, using a mouse model, we describe a dual role for the let-7 microRNAs in the regulation of CD8 T cell responses, where maintenance of the naïve phenotype in CD8 T cells requires high levels of let-7 expression, while generation of cytotoxic T lymphocytes depends upon T cell receptor mediated let-7 downregulation. Decrease of let-7 expression in activated T cells enhances clonal expansion and the acquisition of effector function through derepression of the let-7 targets, including Myc and Eomesodermin. Ultimately, we have identified a novel let-7 mediated mechanism, which acts as a molecular brake controlling the magnitude of CD8 T cell responses.

Article and author information

Author details

  1. Alexandria C Wells

    Department of Veterinary and Animal Sciences, University of Massachusetts, Amherst, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Keith A Daniels

    Department of Pathology, University of Massachusetts Medical School, Worcester, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Constance C Angelou

    Department of Veterinary and Animal Sciences, University of Massachusetts, Amherst, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Eric Fagerberg

    Department of Veterinary and Animal Sciences, University of Massachusetts, Amherst, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Amy S Burnside

    Department of Veterinary and Animal Sciences, University of Massachusetts, Amherst, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Michele Markstein

    Department of Biology, University of Massachusetts, Amherst, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Dominique Alfandari

    Department of Veterinary and Animal Sciences, University of Massachusetts, Amherst, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-0557-1246
  8. Raymond M Welsh

    Department of Pathology, University of Massachusetts Medical School, Worcester, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Elena L Pobezinskaya

    Department of Veterinary and Animal Sciences, University of Massachusetts, Amherst, United States
    For correspondence
    pobezinskaya@umass.edu
    Competing interests
    The authors declare that no competing interests exist.
  10. Leonid A Pobezinsky

    Department of Veterinary and Animal Sciences, University of Massachusetts, Amherst, United States
    For correspondence
    lpobezinsky@umass.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-6115-3559

Funding

National Multiple Sclerosis Society (PP-1503-03417)

  • Leonid A Pobezinsky

University of Massachusetts Amherst (Start up funds)

  • Leonid A Pobezinsky

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

Ethics

Animal experimentation: This study was performed in accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All of the animals were handled according to approved institutional animal care and use committee (IACUC) protocols (#2014-0045, 2014-0065, 2015-0035) of the University of Massachusetts.

Reviewing Editor

  1. Michael L Dustin, University of Oxford, United Kingdom

Publication history

  1. Received: February 27, 2017
  2. Accepted: July 21, 2017
  3. Accepted Manuscript published: July 24, 2017 (version 1)
  4. Version of Record published: August 9, 2017 (version 2)

Copyright

© 2017, Wells 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. Alexandria C Wells
  2. Keith A Daniels
  3. Constance C Angelou
  4. Eric Fagerberg
  5. Amy S Burnside
  6. Michele Markstein
  7. Dominique Alfandari
  8. Raymond M Welsh
  9. Elena L Pobezinskaya
  10. Leonid A Pobezinsky
(2017)
Modulation of let-7 miRNAs controls the differentiation of effector CD8 T cells
eLife 6:e26398.
https://doi.org/10.7554/eLife.26398

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