ApoB-specific CD4+ T cells in atherosclerosis: MHC-II antigen presentation, T cell plasticity, and immune tolerance.

Despite intensive lipid-lowering therapy, substantial residual cardiovascular risk persists, and antigen-specific adaptive immunity may contribute to the inflammatory burden that remains after lipid levels are controlled. Apolipoprotein B (ApoB)-containing lipoproteins accumulate in the arterial wall and undergo local modification. During this process, ApoB-containing material may be taken up by antigen-presenting cells, processed into self-peptides, and presented through MHC-II molecules to CD4+ T cells. This review focuses on ApoB antigen processing and presentation, the functional heterogeneity of ApoB-reactive CD4+ T cells, and emerging antigen-specific therapeutic approaches. Evidence from selected mouse models and human HLA-restricted systems indicates that ApoB-reactive T cells can acquire FoxP3+ regulatory features. However, under hyperlipidemic conditions and during advanced disease, these regulatory features may overlap with, or be replaced by, T-bet+, memory-like, and pro-inflammatory phenotypes. Human studies using HLA-DR-p18 tetramers, activation-induced marker assays in peripheral blood mononuclear cells, and single-cell TCR analyses have begun to define disease-associated differences in ApoB-reactive T-cell states. Even so, current data do not yet prove longitudinal transitions within the same T-cell clones. Interpretation is further limited by HLA restriction, the rarity of ApoB-reactive cells, and relatively small study cohorts. In preclinical models, ApoB peptide vaccination and mucosal tolerance approaches suggest that antigen-specific immunity can be shifted toward regulation without broad immunosuppression. Taken together, ApoB-specific immunity appears to reflect a changing balance between tolerance and inflammation, influenced by antigen burden, HLA background, antigen-presenting cell status, and lesion stage.