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

Abstract
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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/K^b-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/K^b-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/K^b-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

(2021) Non-deletional CD8+ T cell self-tolerance permits responsiveness but limits tissue damage
NCBI Gene Expression Omnibus, GSE171221.

http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE171221

Article and author information

Author details

Emily N Truckenbrod

Center for Immunology, University of Minnesota Medical School, Minneapolis, United States

Competing interests
No competing interests declared.

"This ORCID iD identifies the author of this article:" 0000-0002-3819-6307
Kristina S Burrack

Center for Immunology, University of Minnesota Medical School, Minneapolis, United States

Competing interests
No competing interests declared.
Todd P Knutson

Minnesota Supercomputing Institute, University of Minnesota Medical School, Minneapolis, United States

Competing interests
No competing interests declared.

"This ORCID iD identifies the author of this article:" 0000-0001-8431-9964
Henrique Borges da Silva

Center for Immunology, University of Minnesota Medical School, Minneapolis, United States

Competing interests
No competing interests declared.
Katharine E Block

Center for Immunology, University of Minnesota Medical School, Minneapolis, United States

Competing interests
No competing interests declared.
Stephen D O'Flanagan

Center for Immunology, University of Minnesota Medical School, Minneapolis, United States

Competing interests
No competing interests declared.
Katie R Stagliano

NIAID, NIH, Bethesda, United States

Competing interests
No competing interests declared.
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..
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..
Kristin R Renkema

Grand Valley State University, Allendale, United States

For correspondence
renkemak@gvsu.edu

Competing interests
No competing interests declared.
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.

"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.