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 apolipoprotein E–deficient (ApoE) mice but their mechanisms of action are unknown. OBJECTIVES:We investigated the roles of bystander T, B, and NK cells; NKT cell–derived interferon-γ, interleukin (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 ApoERag2 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-cell–deficient, and NK cell–deficient ApoERag2γC 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 interferon-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 ApoEJα18 mice. CD4 NKT cells deficient in IL-4, interferon-γ, or IL-21 augmented atherosclerosis in ApoEJα18 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 (vascular cell adhesion molecule) and MCP-1 (monocyte chemotactic protein) were 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 postapoptotic necrosis and inflammation.