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

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.

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.

Metrics

  • 4,053
    views
  • 576
    downloads
  • 71
    citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  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

Share this article

https://doi.org/10.7554/eLife.26398

Further reading

    1. Immunology and Inflammation
    2. Neuroscience
    Yuedan Wang, Ying Li ... Xuan Xiao
    Research Article

    Acute retinal ischemia and ischemia-reperfusion injury are the primary causes of retinal neural cell death and vision loss in retinal artery occlusion (RAO). The absence of an accurate mouse model for simulating the retinal ischemic process has hindered progress in developing neuroprotective agents for RAO. We developed a unilateral pterygopalatine ophthalmic artery occlusion (UPOAO) mouse model using silicone wire embolization combined with carotid artery ligation. The survival of retinal ganglion cells and visual function were evaluated to determine the duration of ischemia. Immunofluorescence staining, optical coherence tomography, and haematoxylin and eosin staining were utilized to assess changes in major neural cell classes and retinal structure degeneration at two reperfusion durations. Transcriptomics was employed to investigate alterations in the pathological process of UPOAO following ischemia and reperfusion, highlighting transcriptomic differences between UPOAO and other retinal ischemia-reperfusion models. The UPOAO model successfully replicated the acute interruption of retinal blood supply observed in RAO. 60 min of Ischemia led to significant loss of major retinal neural cells and visual function impairment. Notable thinning of the inner retinal layer, especially the ganglion cell layer, was evident post-UPOAO. Temporal transcriptome analysis revealed various pathophysiological processes related to immune cell migration, oxidative stress, and immune inflammation during the non-reperfusion and reperfusion periods. A pronounced increase in microglia within the retina and peripheral leukocytes accessing the retina was observed during reperfusion periods. Comparison of differentially expressed genes (DEGs) between the UPOAO and high intraocular pressure models revealed specific enrichments in lipid and steroid metabolism-related genes in the UPOAO model. The UPOAO model emerges as a novel tool for screening pathogenic genes and promoting further therapeutic research in RAO.

    1. Immunology and Inflammation
    Hyun-Chae Lee, Sun-Hee Park ... Kyoung Seob Song
    Research Article

    The gram-negative bacterium lipopolysaccharide (LPS) is frequently administered to generate models of systemic inflammation. However, there are several side effects and no effective treatment for LPS-induced systemic inflammation. PEGylated PDZ peptide based on zonula occludens-1 (ZO-1) was analyzed for its effects on systemic inflammation induced by LPS. PDZ peptide administration led to the restoration of tissue injuries (kidney, liver, and lung) and prevented alterations in biochemical plasma markers. The production of pro-inflammatory cytokines was significantly decreased in the plasma and lung BALF in the PDZ-administered mice. Flow cytometry analysis revealed the PDZ peptide significantly inhibited inflammation, mainly by decreasing the population of M1 macrophages, and neutrophils (immature and mature), and increasing M2 macrophages. Using RNA sequencing analysis, the expression levels of the NF-κB-related proteins were lower in PDZ-treated cells than in LPS-treated cells. In addition, wild-type PDZ peptide significantly increased mitochondrial membrane integrity and decreased LPS-induced mitochondria fission. Interestingly, PDZ peptide dramatically could reduce LPS-induced NF-κB signaling, ROS production, and the expression of M1 macrophage marker proteins, but increased the expression of M2 macrophage marker proteins. These results indicated that PEGylated PDZ peptide inhibits LPS-induced systemic inflammation, reducing tissue injuries and reestablishing homeostasis, and may be a therapeutic candidate against systemic inflammation.