Abstract 359: CD4+ Natural Killer T Cells Promote Atherosclerosis via Cytotoxic Mechanism
CD4+ NKT cells are atherogenic lymphocytes, but the mechanisms by which they promote atherosclerosis are not known. Here we investigated the role of other lymphocytes and NKT cell-derived cytokines and cytotoxins in NKT cell’s atherogenicity. First, CD4+ NKT cells were adoptively transferred into ApoE-/- mice; deficient in T, B cell and NKT cells (ApoE-/- Rag2-/-) and in T, B, NKT and NK cells (ApoE-/-Rag2-/-γc-/-). At the end of 8 week high fat diet, CD4+ NKT cells augmented aortic root atherosclerosis assessed by total intimal lesion area, lipid content and macrophage accumulation in both ApoE-/-Rag2-/- mice and ApoE-/-Rag2-/-γC-/-mice. These data indicate that CD4+ NKT cells can exert atherogenic effects in the absence of other lymphocytes. As NKT cells secrete cytokines and cytotoxins, we next investigated the role of NKT cell-derived cytokines and cytotoxins in atherosclerosis development. CD4+ NKT cells from mice deficient of IFN-γ, IL-4 and IL-21 cytokines and perforin and granzyme B cytotoxins were transferred into NKT cell-deficient ApoE-/-Jα18-/- mice; controls were ApoE-/-Jα18-/- mice that received PBS or wildtype NKT cells. At completion of 8 week high fat diet, wildtype CD4+ NKT cells and those deficient in IL-4, IFN-γ or IL-21 increased total intimal lesion area by ~65%, ~95%, ~80% and ~70% compared to vehicle control mice respectively. In contrast CD4+ NKT cells deficient in perforin or granzyme B failed to augment lesion size, lipid content and macrophage accumulation. Apoptotic cells, necrotic cores and proinflammatory VCAM-1 and MCP-1 were reduced in mice receiving perforin-deficient NKT cells. Our data suggest that CD4+ NKT cells require perforin and granzyme-B for atherosclerosis development, thereby increasing apoptotic and necrotic cells in lesions that in turn augments inflammation. Targeting NKT cell apoptotic cell mediators may be useful in attenuating atherosclerosis.
Author Disclosures: Y. Li: None. K. To: None. P. Kanellakis: None. H. Hosseini: None. V. Deswaerte: None. P. Tipping: None. M. Smyth: None. B. Toh: None. A. Bobik: None. T. Kyaw: None.
- © 2015 by American Heart Association, Inc.