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

Area of Science:

• Immunology
• Cardiovascular Research
• Autoimmunity

Background:

• Atherosclerosis involves CD4+ T-helper cells and Apolipoprotein B (apoB) as an autoantigen.
• While pathogenic T-helper type 1 (T_H1) cells are known, atheroprotective regulatory T cells (Tregs) specific to apoB are suggested in healthy individuals.

Purpose of the Study:

• To investigate the function of apoB-reactive T cells in atherosclerosis.
• To understand the relationship between apoB-reactive Tregs and pathogenic T_H1 cells.

Main Methods:

• Utilized MHC class II tetramers to track single T cells reactive to mouse apo B_978-993 peptide.
• Employed single-cell RNA sequencing and flow cytometry to analyze T cell transcriptomes and phenotypes.
• Conducted adoptive transfer experiments in hyperlipidemic mice.

Main Results:

• ApoB-reactive T cells in healthy mice showed a Treg-like transcriptome, but low FoxP3 expression.
• Single-cell sequencing revealed mixed T_H signatures (T_H1, T_H2, T_H17, Tfh) in apoB+ T cells.
• ApoB+ T cells increased in atherosclerosis, converting to pathogenic T_H1/T_H17 phenotypes with loss of Treg markers.
• Adoptive transfer of apoB+ Tregs did not protect against atherosclerosis.

Conclusions:

• ApoB-reactive T cells exhibit an unexpected mixed phenotype in atherosclerosis.
• The autoimmune response against apoB may initially be protective but becomes dysregulated in disease.
• ApoB-autoreactive Tregs represent a potential cellular target for atherosclerosis treatment.