1. Immunology and Inflammation

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
https://doi.org/10.7554/eLife.65615
Share this article
Cite this article
  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
  2. Download BibTeX
  3. Download .RIS

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.

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).

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

  • 2,549
    views
  • 242
    downloads
  • 10
    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

Categories and tags

Research organism

Further reading

    1. Immunology and Inflammation
    2. Microbiology and Infectious Disease

    Soluble immune mediators orchestrate protective in vitro granulomatous responses across Mycobacterium tuberculosis complex lineages

    Ainhoa Arbués, Sarah Schmidiger ... Damien Portevin
    Research Article

    The members of the Mycobacterium tuberculosis complex (MTBC) causing human tuberculosis comprise 10 phylogenetic lineages that differ in their geographical distribution. The human consequences of this phylogenetic diversity remain poorly understood. Here, we assessed the phenotypic properties at the host-pathogen interface of 14 clinical strains representing five major MTBC lineages. Using a human in vitro granuloma model combined with bacterial load assessment, microscopy, flow cytometry, and multiplexed-bead arrays, we observed considerable intra-lineage diversity. Yet, modern lineages were overall associated with increased growth rate and more pronounced granulomatous responses. MTBC lineages exhibited distinct propensities to accumulate triglyceride lipid droplets—a phenotype associated with dormancy—that was particularly pronounced in lineage 2 and reduced in lineage 3 strains. The most favorable granuloma responses were associated with strong CD4 and CD8 T cell activation as well as inflammatory responses mediated by CXCL9, granzyme B, and TNF. Both of which showed consistent negative correlation with bacterial proliferation across genetically distant MTBC strains of different lineages. Taken together, our data indicate that different virulence strategies and protective immune traits associate with MTBC genetic diversity at lineage and strain level.

    1. Immunology and Inflammation

    Inflammasomes: A tale of two caspases

    Denise M Monack
    Insight

    Macrophages control intracellular pathogens like Salmonella by using two caspase enzymes at different times during infection.

    1. Immunology and Inflammation
    2. Medicine

    Deciphering the preeclampsia-specific immune microenvironment and the role of pro-inflammatory macrophages at the maternal–fetal interface

    Haiyi Fei, Xiaowen Lu ... Lingling Jiang
    Research Article

    Preeclampsia (PE), a major cause of maternal and perinatal mortality with highly heterogeneous causes and symptoms, is usually complicated by gestational diabetes mellitus (GDM). However, a comprehensive understanding of the immune microenvironment in the placenta of PE and the differences between PE and GDM is still lacking. In this study, cytometry by time of flight indicated that the frequencies of memory-like Th17 cells (CD45RA−CCR7+IL-17A+CD4+), memory-like CD8+ T cells (CD38+CXCR3−CCR7+Helios−CD127−CD8+) and pro-inflam Macs (CD206−CD163−CD38midCD107alowCD86midHLA-DRmidCD14+) were increased, while the frequencies of anti-inflam Macs (CD206+CD163−CD86midCD33+HLA-DR+CD14+) and granulocyte myeloid-derived suppressor cells (gMDSCs, CD11b+CD15hiHLA-DRlow) were decreased in the placenta of PE compared with that of normal pregnancy (NP), but not in that of GDM or GDM&PE. The pro-inflam Macs were positively correlated with memory-like Th17 cells and memory-like CD8+ T cells but negatively correlated with gMDSCs. Single-cell RNA sequencing revealed that transferring the F4/80+CD206− pro-inflam Macs with a Folr2+Ccl7+Ccl8+C1qa+C1qb+C1qc+ phenotype from the uterus of PE mice to normal pregnant mice induced the production of memory-like IL-17a+Rora+Il1r1+TNF+Cxcr6+S100a4+CD44+ Th17 cells via IGF1–IGF1R, which contributed to the development and recurrence of PE. Pro-inflam Macs also induced the production of memory-like CD8+ T cells but inhibited the production of Ly6g+S100a8+S100a9+Retnlg+Wfdc21+ gMDSCs at the maternal–fetal interface, leading to PE-like symptoms in mice. In conclusion, this study revealed the PE-specific immune cell network, which was regulated by pro-inflam Macs, providing new ideas about the pathogenesis of PE.