Cytotoxic and Proinflammatory CD8+ T Lymphocytes Promote Development of Vulnerable Atherosclerotic Plaques in ApoE-/- Mice
Background—Heart attacks and strokes, leading causes of deaths globally, arise from thrombotic occlusion of ruptured vulnerable atherosclerotic plaques characterized by abundant apoptosis, large necrotic cores derived from inefficient apoptotic cell clearance, thin fibrous caps and focal inflammation. The genesis of apoptosis and necrotic cores in these vulnerable atherosclerotic plaques remains unknown. Cytotoxic CD8+ T lymphocytes represent up to 50% of leucocytes in advanced human plaques and dominate early immune responses in mouse lesions yet their role in atherosclerosis also remains unresolved.
Methods and Results—CD8+ T lymphocyte depletion by CD8α or CD8β monoclonal antibody in Apolipoprotein E-deficient (ApoE-/-) mice fed a high fat diet ameliorated atherosclerosis by reducing lipid and macrophage accumulation, apoptosis, necrotic cores, and MCP1, IL1β, IFNγ and VCAM-1. Transfer of CD8+ T cells into lymphocyte-deficient ApoE-/- mice partially reconstituted CD8+ T cells in lymphoid compartments and was associated with CD8+ T cell infiltration in lesions, increased lipid and macrophage accumulation, apoptotic cells, necrotic cores and IL1β in atherosclerotic lesions. Transfer of CD8+ T cells deficient in perforin, granzyme-B or TNFα but not IFNγ failed to increase atherosclerotic lesions despite partial reconstitution in the lymphoid system and presence in atherosclerotic lesions. Macrophages, smooth muscle cells and endothelial cells were identified as apoptotic targets.
Conclusions—We conclude that CD8+ T lymphocytes promote development of vulnerable atherosclerotic plaques by perforin- and granzyme B-mediated apoptosis of macrophages, smooth muscle cells and endothelial cells that in turn leads to necrotic core formation and further augment inflammation by TNFαsecretion.
- Received January 14, 2013.
- Accepted January 17, 2013.
- Copyright © 2013, Circulation