Dataset Information

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

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 (T_H1) cells with proinflammatory cytokine secretion. Clinical data suggest the existence of apoB-specific CD4⁺ T cells with an atheroprotective, regulatory T cell (T_reg) phenotype in healthy individuals. Yet, the function of apoB-reactive T_regs and their relationship with pathogenic T_H1 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 B_978-993 (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 T_reg-like transcriptome, although only 21% of all apoB⁺ T cells expressed the T_reg transcription factor FoxP3 (Forkhead Box P3) protein as detected by flow cytometry. In single-cell RNA sequencing, apoB⁺ T cells formed several clusters with mixed T_H signatures that suggested overlapping multilineage phenotypes with pro- and anti-inflammatory transcripts of T_H1, T helper cell type 2 (T_H2), and T helper cell type 17 (T_H17), and of follicular-helper T cells. ApoB⁺ T cells were increased in mice and humans with atherosclerosis and progressively converted into pathogenic T_H1/T_H17-like cells with proinflammatory properties and only a residual T_reg transcriptome. Plaque T cells that expanded during progression of atherosclerosis consistently showed a mixed T_H1/T_H17 phenotype in single-cell RNA sequencing. In addition, we observed a loss of FoxP3 in a fraction of apoB⁺ T_regs in lineage tracing of hyperlipidemic Apoe^-/- mice. In adoptive transfer experiments, converting apoB⁺ T_regs failed 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 T_regs as a novel cellular target in atherosclerosis.

SUBMITTER: Wolf D

PROVIDER: S-EPMC7515473 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

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Publications

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

Wolf Dennis D Gerhardt Teresa T Winkels Holger H Michel Nathaly Anto NA Pramod Akula Bala AB Ghosheh Yanal Y Brunel Simon S Buscher Konrad K Miller Jacqueline J McArdle Sara S Baas Livia L Kobiyama Kouji K Vassallo Melanie M Ehinger Erik E Dileepan Thamotharampillai T Ali Amal A Schell Maximilian M Mikulski Zbigniew Z Sidler Daniel D Kimura Takayuki T Sheng Xia X Horstmann Hauke H Hansen Sophie S Mitre Lucia Sol LS Stachon Peter P Hilgendorf Ingo I Gaddis Dalia E DE Hedrick Catherine C Benedict Chris A CA Peters Bjoern B Zirlik Andreas A Sette Alessandro A Ley Klaus K

Circulation 20200724 13

<h4>Background</h4>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 ...[more]

PMID: 32703007

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Project description:IntroductionAtherosclerosis is a major pathological condition that underlies many cardiovascular diseases (CVDs). Its etiology involves breach of tolerance to self, leading to clonal expansion of autoreactive apolipoprotein B (APOB)-reactive CD4+T cells that correlates with clinical CVD. The T-cell receptor (TCR) sequences that mediate activation of APOB-specific CD4+T cells are unknown.MethodsIn a previous study, we had profiled the hypervariable complementarity determining region 3 (CDR3) of CD4+T cells that respond to six immunodominant APOB epitopes in most donors. Here, we comprehensively analyze this dataset of 149,065 APOB-reactive and 199,211 non-reactive control CDR3s from six human leukocyte antigen-typed donors.ResultsWe identified 672 highly expanded (frequency threshold > 1.39E-03) clones that were significantly enriched in the APOB-reactive group as compared to the controls (log10 odds ratio ≥1, Fisher's test p < 0.01). Analysis of 114,755 naïve, 91,001 central memory (TCM) and 29,839 effector memory (TEM) CDR3 sequences from the same donors revealed that APOB+ clones can be traced to the complex repertoire of unenriched blood T cells. The fraction of APOB+ clones that overlapped with memory CDR3s ranged from 2.2% to 46% (average 16.4%). This was significantly higher than their overlap with the naïve pool, which ranged from 0.7% to 2% (average 1.36%). CDR3 motif analysis with the machine learning-based in-silico tool, GLIPHs (grouping of lymphocyte interactions by paratope hotspots), identified 532 APOB+ motifs. Analysis of naïve and memory CDR3 sequences with GLIPH revealed that ~40% (209 of 532) of these APOB+ motifs were enriched in the memory pool. Network analysis with Cytoscape revealed extensive sharing of the memory-affiliated APOB+ motifs across multiple donors. We identified six motifs that were present in TCM and TEM CDR3 sequences from >80% of the donors and were highly enriched in the APOB-reactive TCR repertoire.DiscussionThe identified APOB-reactive expanded CD4+T cell clones and conserved motifs can be used to annotate and track human atherosclerosis-related autoreactive CD4+T cells and measure their clonal expansion.

Project description:Atherosclerosis is a major pathological condition that underlies many cardiovascular diseases (CVDs). Its etiology involves breach of tolerance to self, leading to clonal expansion of autoreactive apolipoprotein B (APOB)–reactive CD4+T cells that correlates with clinical CVD. The T-cell receptor (TCR) sequences that mediate activation of APOB-specific CD4+T cells are unknown. Methods: In a previous study, we had profiled the hypervariable complementarity determining region 3 (CDR3) of CD4+T cells that respond to six immunodominant APOB epitopes in most donors. Here, we comprehensively analyze this dataset of 149,065 APOB-reactive and 199,211 non-reactive control CDR3s from six human leukocyte antigen–typed donors. Results: We identified 672 highly expanded (frequency threshold > 1.39E-03) clones that were significantly enriched in the APOB-reactive group as compared to the controls (log10 odds ratio ≥1, Fisher’s test p < 0.01). Analysis of 114,755 naïve, 91,001 central memory (TCM) and 29,839 effector memory (TEM) CDR3 sequences from the same donors revealed that APOB+ clones can be traced to the complex repertoire of unenriched blood T cells. The fraction of APOB+ clones that overlapped with memory CDR3s ranged from 2.2% to 46% (average 16.4%). This was significantly higher than their overlap with the naïve pool, which ranged from 0.7% to 2% (average 1.36%). CDR3 motif analysis with the machine learning–based in-silico tool, GLIPHs (grouping of lymphocyte interactions by paratope hotspots), identified 532 APOB+ motifs. Analysis of naïve and memory CDR3 sequences with GLIPH revealed that ~40% (209 of 532) of these APOB+motifs were enriched in the memory pool. Network analysis with Cytoscape revealed extensive sharing of the memory-affiliated APOB+ motifs across multiple donors. We identified six motifs that were present in TCM and TEM CDR3 sequences from >80% of the donors and were highly enriched in the APOB-reactive TCR repertoire. Discussion: The identified APOB-reactive expanded CD4+T cell clones and conserved motifs can be used to annotate and track human atherosclerosis-related autoreactive CD4+T cells and measure their clonal expansion.