Pathogenic Autoimmunity in Atherosclerosis Evolves from Initially Protective Apolipoprotein B100-Reactive CD4+T-Regulatory Cells

Dennis Wolf, Teresa Gerhardt, Holger Winkels, Nathaly Anto Michel, Akula Bala Pramod, Yanal Ghosheh, Simon Brunel, Konrad Buscher, Jacqueline Miller, Sara McArdle, Livia Baas, Kouji Kobiyama, Melanie Vassallo, Erik Ehinger, Thamotharampillai Dileepan, Amal Ali, Maximilian Schell, Zbigniew Mikulski, Daniel Sidler, Takayuki KimuraXia Sheng, Hauke Horstmann, Sophie Hansen, Lucia Sol Mitre, Peter Stachon, Ingo Hilgendorf, Dalia E. Gaddis, Catherine Hedrick, Chris A. Benedict, Bjoern Peters, Andreas Zirlik, Alessandro Sette, Klaus Ley

Research output: Contribution to journalArticlepeer-review

6 Scopus citations

Abstract

Background: Throughout the inflammatory response that accompanies atherosclerosis, autoreactive CD4+T-helper cells accumulate in the atherosclerotic plaque. Apolipoprotein B100(apoB), the core protein of low-density lipoprotein, is an autoantigen that drives the generation of pathogenic T-helper type 1 (TH1) cells with proinflammatory cytokine secretion. Clinical data suggest the existence of apoB-specific CD4+T cells with an atheroprotective, regulatory T cell (Treg) phenotype in healthy individuals. Yet, the function of apoB-reactive Tregsand their relationship with pathogenic TH1 cells remain unknown. Methods: To interrogate the function of autoreactive CD4+T cells in atherosclerosis, we used a novel tetramer of major histocompatibility complex II to track T cells reactive to the mouse self-peptide apo B978-993(apoB+) at the single-cell level. Results: We found that apoB+T cells build an oligoclonal population in lymph nodes of healthy mice that exhibit a Treg-like transcriptome, although only 21% of all apoB+T cells expressed the Tregtranscription factor FoxP3 (Forkhead Box P3) protein as detected by flow cytometry. In single-cell RNA sequencing, apoB+T cells formed several clusters with mixed THsignatures that suggested overlapping multilineage phenotypes with pro- and anti-inflammatory transcripts of TH1, T helper cell type 2 (TH2), and T helper cell type 17 (TH17), and of follicular-helper T cells. ApoB+T cells were increased in mice and humans with atherosclerosis and progressively converted into pathogenic TH1/TH17-like cells with proinflammatory properties and only a residual Tregtranscriptome. Plaque T cells that expanded during progression of atherosclerosis consistently showed a mixed TH1/TH17 phenotype in single-cell RNA sequencing. In addition, we observed a loss of FoxP3 in a fraction of apoB+Tregsin lineage tracing of hyperlipidemic Apoe-/-mice. In adoptive transfer experiments, converting apoB+Tregsfailed to protect from atherosclerosis. Conclusions: Our results demonstrate an unexpected mixed phenotype of apoB-reactive autoimmune T cells in atherosclerosis and suggest an initially protective autoimmune response against apoB with a progressive derangement in clinical disease. These findings identify apoB autoreactive Tregsas a novel cellular target in atherosclerosis.

Original languageEnglish (US)
Pages (from-to)1279-1293
Number of pages15
JournalCirculation
Volume142
Issue number13
DOIs
StatePublished - Sep 29 2020

Bibliographical note

Publisher Copyright:
© 2020 Lippincott Williams and Wilkins. All rights reserved.

Copyright:
Copyright 2020 Elsevier B.V., All rights reserved.

Keywords

  • T-lymphocytes
  • T-lymphocytes, regulatory
  • apolipoprotein B-100
  • atherosclerosis
  • autoimmunity

PubMed: MeSH publication types

  • Journal Article

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