T cells are found in atherosclerotic plaques, with evidence supporting a potential role for CD8+ T cells in atherogenesis. Prior studies provide evidence of low‐density lipoprotein and apoB‐100 reactive T cells, yet specific epitopes relevant to the disease remain to be defined. The current study was undertaken to identify and characterize endogenous, antigen‐specific CD8+ T cells in atherosclerosis.

A peptide fragment of apoB‐100 that tested positive for binding to the mouse MHC‐I allele H2K^b was used to generate a fluorescent‐labeled H2K^b pentamer and tested in apoE^−/− mice. H2K^b pentamer(+)CD8+ T cells were higher in apoE^−/− mice fed an atherogenic diet compared with those fed a normal chow. H2K^b pentamer (+)CD8+ T cells in atherogenic diet–fed mice had significantly increased effector memory phenotype with a shift in Vβ profile. H2K^b pentamer blocked lytic activity of CD8+ T cells from atherogenic diet–fed mice. Immunization of age‐matched apoE^−/− mice with the apoB‐100 peptide altered the immune‐dominant epitope of CD8+ T cells and reduced atherosclerosis.

Our study provides evidence of a self‐reactive, antigen‐specific CD8+ T‐cell population in apoE^−/− mice. Immune modulation using the peptide antigen reduced atherosclerosis in apoE^−/− mice.