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

  • 2,387
    views
  • 235
    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

Categories and tags

Research organism

Further reading

    1. Chromosomes and Gene Expression
    2. Immunology and Inflammation

    Dynamic chromatin architecture identifies new autoimmune-associated enhancers for IL2 and novel genes regulating CD4+ T cell activation

    Matthew C Pahl, Prabhat Sharma ... Andrew D Wells
    Research Article

    Genome-wide association studies (GWAS) have identified hundreds of genetic signals associated with autoimmune disease. The majority of these signals are located in non-coding regions and likely impact cis-regulatory elements (cRE). Because cRE function is dynamic across cell types and states, profiling the epigenetic status of cRE across physiological processes is necessary to characterize the molecular mechanisms by which autoimmune variants contribute to disease risk. We localized risk variants from 15 autoimmune GWAS to cRE active during TCR-CD28 co-stimulation of naïve human CD4+ T cells. To characterize how dynamic changes in gene expression correlate with cRE activity, we measured transcript levels, chromatin accessibility, and promoter–cRE contacts across three phases of naive CD4+ T cell activation using RNA-seq, ATAC-seq, and HiC. We identified ~1200 protein-coding genes physically connected to accessible disease-associated variants at 423 GWAS signals, at least one-third of which are dynamically regulated by activation. From these maps, we functionally validated a novel stretch of evolutionarily conserved intergenic enhancers whose activity is required for activation-induced IL2 gene expression in human and mouse, and is influenced by autoimmune-associated genetic variation. The set of genes implicated by this approach are enriched for genes controlling CD4+ T cell function and genes involved in human inborn errors of immunity, and we pharmacologically validated eight implicated genes as novel regulators of T cell activation. These studies directly show how autoimmune variants and the genes they regulate influence processes involved in CD4+ T cell proliferation and activation.

    1. Cell Biology
    2. Immunology and Inflammation

    Arpin deficiency increases actomyosin contractility and vascular permeability

    Armando Montoya-Garcia, Idaira M Guerrero-Fonseca ... Michael Schnoor
    Research Article

    Arpin was discovered as an inhibitor of the Arp2/3 complex localized at the lamellipodial tip of fibroblasts, where it regulated migration steering. Recently, we showed that arpin stabilizes the epithelial barrier in an Arp2/3-dependent manner. However, the expression and functions of arpin in endothelial cells (EC) have not yet been described. Arpin mRNA and protein are expressed in EC and downregulated by pro-inflammatory cytokines. Arpin depletion in Human Umbilical Vein Endothelial Cells causes the formation of actomyosin stress fibers leading to increased permeability in an Arp2/3-independent manner. Instead, inhibitors of ROCK1 and ZIPK, kinases involved in the generation of stress fibers, normalize the loss-of-arpin effects on actin filaments and permeability. Arpin-deficient mice are viable but show a characteristic vascular phenotype in the lung including edema, microhemorrhage, and vascular congestion, increased F-actin levels, and vascular permeability. Our data show that, apart from being an Arp2/3 inhibitor, arpin is also a regulator of actomyosin contractility and endothelial barrier integrity.

    1. Immunology and Inflammation

    The common Sting1 HAQ, AQ alleles rescue CD4 T cellpenia, restore T-regs, and prevent SAVI (N153S) inflammatory disease in mice

    Alexandra a Aybar-Torres, Lennon A Saldarriaga ... Lei Jin
    Research Article

    The significance of STING1 gene in tissue inflammation and cancer immunotherapy has been increasingly recognized. Intriguingly, common human STING1 alleles R71H-G230A-R293Q (HAQ) and G230A-R293Q (AQ) are carried by ~60% of East Asians and ~40% of Africans, respectively. Here, we examine the modulatory effects of HAQ, AQ alleles on STING-associated vasculopathy with onset in infancy (SAVI), an autosomal dominant, fatal inflammatory disease caused by gain-of-function human STING1 mutations. CD4 T cellpenia is evident in SAVI patients and mouse models. Using Sting1 knock-in mice expressing common human STING1 alleles HAQ, AQ, and Q293, we found that HAQ, AQ, and Q293 splenocytes resist STING1-mediated cell death ex vivo, establishing a critical role of STING1 residue 293 in cell death. The HAQ/SAVI(N153S) and AQ/SAVI(N153S) mice did not have CD4 T cellpenia. The HAQ/SAVI(N153S), AQ/SAVI(N153S) mice have more (~10-fold, ~20-fold, respectively) T-regs than WT/SAVI(N153S) mice. Remarkably, while they have comparable TBK1, IRF3, and NFκB activation as the WT/SAVI, the AQ/SAVI mice have no tissue inflammation, regular body weight, and normal lifespan. We propose that STING1 activation promotes tissue inflammation by depleting T-regs cells in vivo. Billions of modern humans have the dominant HAQ, AQ alleles. STING1 research and STING1-targeting immunotherapy should consider STING1 heterogeneity in humans.