Background:
Throughout the inflammatory response that accompanies atherosclerosis, autoreactive CD4
+
T-helper cells accumulate in the atherosclerotic plaque. Apolipoprotein B
100
(apoB), the core protein of low-density lipoprotein, is an autoantigen that drives the generation of pathogenic T-helper type 1 (T
H
1) 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
H
1 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
H
1, T helper cell type 2 (T
H
2), and T helper cell type 17 (T
H
17), and of follicular-helper T cells. ApoB
+
T cells were increased in mice and humans with atherosclerosis and progressively converted into pathogenic T
H
1/T
H
17-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
H
1/T
H
17 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.
Generation of IL-8 and IL-9 Producing CD4+T Cells Is Affected by Th17 Polarizing Conditions and AHR Ligands
