CD4+ Natural Killer T Cells Potently Augment Aortic Root Atherosclerosis by Perforin- and Granzyme B-Dependent Cytotoxicity
Rationale: CD4+ Natural Killer T (NKT) cells augment atherosclerosis in ApoE-/- mice but their mechanisms of action are unknown.
Objective: We investigated the roles of bystander T, B and NK cells, NKT cell derived IFN-γ, IL-4 and IL-21 cytokines and NKT cell derived perforin and granzyme B cytotoxins in promoting CD4+ NKT cell atherogenicity.
Methods and Results: Transfer of CD4+ NKT cells into T and B cell-deficient ApoE-/-Rag2-/- mice augmented aortic root atherosclerosis by ~75% that was ~30% of lesions in ApoE-/- mice; macrophage accumulation similarly increased. Transferred NKT cells were identified in the liver and atherosclerotic lesions of recipient mice. Transfer of CD4+ NKT cells into T, B and NK cell-deficient ApoE-/-Rag2-/-γC-/- mice also augmented atherosclerosis. These data indicate that CD4+ NKT cells can exert proatherogenic effects independent of other lymphocytes. To investigate the role of NKT cell-derived IFN-γ, IL-4 and IL-21 cytokines and perforin and granzyme B cytotoxins, CD4+ NKT cells from mice deficient in these molecules were transferred into NKT cell-deficient ApoE-/-Jα18-/- mice. CD4+ NKT cells deficient in IL-4, IFN-γ or IL-21 augmented atherosclerosis in ApoE-/-Jα18-/- mice by ~95%, ~80% and ~70% respectively. Transfer of CD4+ NKT cells deficient in perforin or granzyme B failed to augment atherosclerosis. Apoptotic cells, necrotic cores and proinflammatory VCAM-1 and MCP-1were reduced in mice receiving perforin-deficient NKT cells. CD4+ NKT cells are twice as potent as CD4+ T cells in promoting atherosclerosis
Conclusions: CD4+ NKT cells potently promote atherosclerosis by perforin and granzyme-B dependent apoptosis that increases post-apoptotic necrosis and inflammation.
- Received July 6, 2014.
- Revision received November 12, 2014.
- Accepted November 14, 2014.