CD8+ T Cells Regulate Monopoiesis and Circulating Ly6Chigh Monocyte Levels in Atherosclerosis in Mice
Rationale: Pro-inflammatory adaptive immune responses are recognized as major drivers of atherosclerotic lesion formation. Although CD8+ T cells have recently been proposed as a pro-atherogenic cell subset, their full scope of actions remains to be elucidated.
Objective: We here addressed the contribution of CD8+ T cells to monocyte trafficking in atherosclerosis.
Methods and Results: We observed that CD8+ T cells express pro-inflammatory cytokines (IFNγ, TNFα, IL-12) within atherosclerotic lesions and spleens of high fat diet (HFD)-fed low density lipoprotein receptor-deficient (Ldlr-/-) mice. Antibody-mediated CD8+ T cell-depletion in HFD-fed Ldlr-/-mice decreased atherosclerotic plaque formation, associated with decreased macrophage accumulation within lesions. Despite a reduction in vascular CCL2 and CXCL1 expression, CD8+ T cell depletion did not directly affect monocyte recruitment to inflamed vessels. However, CD8+ T cell depletion decreased CCL2 serum concentrations and circulating Ly6Chigh 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 IFNγ neutralization, showing a role for IFNγ.
Conclusions: 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 pro-atherogenic innate immune cell responses in atherosclerosis.
- Received June 16, 2014.
- Revision received May 13, 2015.
- Accepted May 19, 2015.