CD8+ T cell self-tolerance permits responsiveness but limits tissue damage

  1. Emily N Truckenbrod
  2. Kristina S Burrack
  3. Todd P Knutson
  4. Henrique Borges da Silva
  5. Katharine E Block
  6. Stephen D O'Flanagan
  7. Katie R Stagliano
  8. Arthur A Hurwitz
  9. Ross B Fulton
  10. Kristin R Renkema  Is a corresponding author
  11. Stephen C Jameson  Is a corresponding author
  1. University of Minnesota Medical School, United States
  2. NIH, United States
  3. Agentus Therapeutics, United States
  4. Grand Valley State University, United States

Abstract

Self-specific CD8+ T cells can escape clonal deletion, but the properties and capabilities of such cells in a physiological setting are unclear. We characterized polyclonal CD8+ T cells specific for the melanocyte antigen tyrosinase-related protein 2 (Trp2) in mice expressing or lacking this enzyme (due to deficiency in Dct, which encodes Trp2). Phenotypic and gene expression profiles of pre-immune Trp2/Kb-specific cells were similar; the size of this population was only slightly reduced in wild-type (WT) compared to Dct-deficient (Dct-/-) mice. Despite comparable initial responses to Trp2 immunization, WT Trp2/Kb-specific cells showed blunted expansion and less readily differentiated into a CD25+ proliferative population. Functional self-tolerance clearly emerged when assessing immunopathology: adoptively transferred WT Trp2/Kb-specific cells mediated vitiligo much less efficiently. Hence, CD8+ T cell self-specificity is poorly predicted by precursor frequency, phenotype or even initial responsiveness, while deficient activation-induced CD25 expression and other gene expression characteristics may help to identify functionally tolerant cells.

Data availability

NextGen sequencing data has being deposited at GEO: Code GSE171221.

The following data sets were generated

Article and author information

Author details

  1. Emily N Truckenbrod

    Center for Immunology, University of Minnesota Medical School, Minneapolis, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-3819-6307
  2. Kristina S Burrack

    Center for Immunology, University of Minnesota Medical School, Minneapolis, United States
    Competing interests
    No competing interests declared.
  3. Todd P Knutson

    Minnesota Supercomputing Institute, University of Minnesota Medical School, Minneapolis, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-8431-9964
  4. Henrique Borges da Silva

    Center for Immunology, University of Minnesota Medical School, Minneapolis, United States
    Competing interests
    No competing interests declared.
  5. Katharine E Block

    Center for Immunology, University of Minnesota Medical School, Minneapolis, United States
    Competing interests
    No competing interests declared.
  6. Stephen D O'Flanagan

    Center for Immunology, University of Minnesota Medical School, Minneapolis, United States
    Competing interests
    No competing interests declared.
  7. Katie R Stagliano

    NIAID, NIH, Bethesda, United States
    Competing interests
    No competing interests declared.
  8. Arthur A Hurwitz

    Immunology, Agentus Therapeutics, Lexington, United States
    Competing interests
    Arthur A Hurwitz, Arthur A Hurwitz is affiliated with AgenTus Therapeutics, Inc. The author has no financial interests to declare..
  9. Ross B Fulton

    Center for Immunology, University of Minnesota Medical School, Minneapolis, United States
    Competing interests
    Ross B Fulton, Ross B. Fulton is affiliated with HiFiBio, Inc. The author has no financial interests to declare..
  10. Kristin R Renkema

    Grand Valley State University, Allendale, United States
    For correspondence
    renkemak@gvsu.edu
    Competing interests
    No competing interests declared.
  11. Stephen C Jameson

    Center for Immunology, University of Minnesota Medical School, Minneapolis, United States
    For correspondence
    james024@umn.edu
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9137-1146

Funding

National Institute of Allergy and Infectious Diseases (R01AI140631)

  • Stephen C Jameson

National Institute of Allergy and Infectious Diseases (P01AI035296)

  • Stephen C Jameson

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

Reviewing Editor

  1. Gabrielle T Belz, The University of Queensland, Australia

Ethics

Animal experimentation: This study was performed in strict accordance with the NIH Guide for the Care and Use of Laboratory Animals and handled according to protocols approved but the University of Minnesota IACUC (#1709-35136A and #2007-38243A).

Version history

  1. Received: December 9, 2020
  2. Accepted: April 29, 2021
  3. Accepted Manuscript published: April 30, 2021 (version 1)
  4. Version of Record published: May 21, 2021 (version 2)

Copyright

This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.

Metrics

  • 2,265
    views
  • 225
    downloads
  • 9
    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. Emily N Truckenbrod
  2. Kristina S Burrack
  3. Todd P Knutson
  4. Henrique Borges da Silva
  5. Katharine E Block
  6. Stephen D O'Flanagan
  7. Katie R Stagliano
  8. Arthur A Hurwitz
  9. Ross B Fulton
  10. Kristin R Renkema
  11. Stephen C Jameson
(2021)
CD8+ T cell self-tolerance permits responsiveness but limits tissue damage
eLife 10:e65615.
https://doi.org/10.7554/eLife.65615

Share this article

https://doi.org/10.7554/eLife.65615

Further reading

    1. Immunology and Inflammation
    Tong Feng, Qi Zhang ... Qiao-Feng Wu
    Research Article

    Osteoarthritis (OA) is a degenerative disease with a high prevalence in the elderly population, but our understanding of its mechanisms remains incomplete. Analysis of serum exosomal small RNA sequencing data from clinical patients and gene expression data from OA patient serum and cartilage obtained from the GEO database revealed a common dysregulated miRNA, miR-199b-5p. In vitro cell experiments demonstrated that miR-199b-5p inhibits chondrocyte vitality and promotes extracellular matrix degradation. Conversely, inhibition of miR-199b-5p under inflammatory conditions exhibited protective effects against damage. Local viral injection of miR-199b-5p into mice induced a decrease in pain threshold and OA-like changes. In an OA model, inhibition of miR-199b-5p alleviated the pathological progression of OA. Furthermore, bioinformatics analysis and experimental validation identified Gcnt2 and Fzd6 as potential target genes of MiR-199b-5p. Thus, these results indicated that MiR-199b-5p/Gcnt2 and Fzd6 axis might be a novel therapeutic target for the treatment of OA.

    1. Immunology and Inflammation
    Phillip A Erice, Xinyan Huang ... Antony Rodriguez
    Research Article

    Environmental air irritants including nanosized carbon black (nCB) can drive systemic inflammation, promoting chronic obstructive pulmonary disease (COPD) and emphysema development. The let-7 microRNA (Mirlet7 miRNA) family is associated with IL-17-driven T cell inflammation, a canonical signature of lung inflammation. Recent evidence suggests the Mirlet7 family is downregulated in patients with COPD, however, whether this repression conveys a functional consequence on emphysema pathology has not been elucidated. Here, we show that overall expression of the Mirlet7 clusters, Mirlet7b/Mirlet7c2 and Mirlet7a1/Mirlet7f1/Mirlet7d, are reduced in the lungs and T cells of smokers with emphysema as well as in mice with cigarette smoke (CS)- or nCB-elicited emphysema. We demonstrate that loss of the Mirlet7b/Mirlet7c2 cluster in T cells predisposed mice to exaggerated CS- or nCB-elicited emphysema. Furthermore, ablation of the Mirlet7b/Mirlet7c2 cluster enhanced CD8+IL17a+ T cells (Tc17) formation in emphysema development in mice. Additionally, transgenic mice overexpressing Mirlet7g in T cells are resistant to Tc17 and CD4+IL17a+ T cells (Th17) development when exposed to nCB. Mechanistically, our findings reveal the master regulator of Tc17/Th17 differentiation, RAR-related orphan receptor gamma t (RORγt), as a direct target of Mirlet7 in T cells. Overall, our findings shed light on the Mirlet7/RORγt axis with Mirlet7 acting as a molecular brake in the generation of Tc17 cells and suggest a novel therapeutic approach for tempering the augmented IL-17-mediated response in emphysema.