Proinflammatory adaptive immune responses are recognized as major drivers of atherosclerotic lesion formation. Although CD8⁺ T cells have recently been proposed as a proatherogenic cell subset, their full scope of actions remains to be elucidated.

We here addressed the contribution of CD8⁺ T cells to monocyte trafficking in atherosclerosis.

We observed that CD8⁺ T cells express proinflammatory cytokines (interferon-γ, tumor necrosis factor-α, and interleukin-12) within atherosclerotic lesions and spleens of high-fat diet–fed low-density lipoprotein receptor–deficient (Ldlr^−/−) mice. Antibody-mediated CD8⁺ T-cell depletion in high-fat diet–fed Ldlr^−/− mice decreased atherosclerotic plaque formation, associated with decreased macrophage accumulation within lesions. Despite a reduction in vascular chemokine (CC-motif) ligand 2 and chemokine (CXC-motif) ligand 1 expression, CD8⁺ T-cell depletion did not directly affect monocyte recruitment to inflamed vessels. However, CD8⁺ T-cell depletion decreased chemokine (CC-motif) ligand serum concentrations and circulating Ly6C^high monocyte counts. We further evidenced that CD8⁺ T-cell depletion decreased levels of mature monocytes and myeloid granulocyte–monocyte progenitors in the bone marrow and spleen of hypercholesterolemic mice, effects that were partially reproduced by interferon-γ neutralization, showing a role for interferon-γ.

These data suggest that CD8⁺ T cells promote atherosclerosis by controlling monopoiesis and circulating monocyte levels, which ultimately contributes to plaque macrophage burden without affecting direct monocyte recruitment, identifying this cell subset as a critical regulator of proatherogenic innate immune cell responses in atherosclerosis.