CD4+ Natural Killer T Cells Potently Augment Aortic Root Atherosclerosis by Perforin- and Granzyme B-Dependent Cytotoxicity. Issue 2 (16th January 2015)

• Record Type: Journal Article
• Authors: Li, Yi; To, Kelly; Kanellakis, Peter; Hosseini, Hamid; Deswaerte, Virginie; Tipping, Peter; Smyth, Mark J.; Toh, Ban-Hock; Bobik, Alexander; Kyaw, Tin
• Is Part Of: Circulation research. Volume 116:Issue 2(2015)
• Publication Date: 2015-01-16
• Subjects: Cardiovascular system -- Periodicals; Blood -- Circulation -- Periodicals; Blood Circulation; Cardiovascular System; Vascular Diseases; Sang -- Circulation -- Périodiques; Appareil cardiovasculaire -- Périodiques; 612.1
• DOI: 10.1161/CIRCRESAHA.116.304734
• Languages: English
• ISSNs: 0009-7330

Abstract

<abstract> <title> <x xml:space="preserve">Abstract</x> </title> <sec> <title> <underline>Rationale:</underline> </title> <p>CD4<sup>+</sup> natural killer T (NKT) cells augment atherosclerosis in apolipoprotein E–deficient (<italic>ApoE</italic>)<sup>−/−</sup> mice but their mechanisms of action are unknown.</p> </sec> <sec> <title> <underline>Objectives:</underline> </title> <p>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<sup>+</sup> NKT cell atherogenicity.</p> </sec> <sec> <title> <underline>Methods and Results:</underline> </title> <p>Transfer of CD4<sup>+</sup> NKT cells into T- and B-cell–deficient <italic>ApoE<sup>−/−</sup>Rag2<sup>−/−</sup></italic> mice augmented aortic root atherosclerosis by ≈75% that was ≈30% of lesions in ApoE<sup>−/−</sup> mice; macrophage accumulation similarly increased. Transferred NKT cells were identified in the liver and atherosclerotic lesions of recipient mice. Transfer of CD4<sup>+</sup> NKT cells into T-, B-cell–deficient, and NK cell–deficient <italic>ApoE<sup>−/−</sup>Rag2<sup>−/−</sup>γC<sup>−/−</sup></italic> mice also augmented atherosclerosis. These data indicate that CD4<sup>+</sup> 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<sup>+</sup> NKT cells from mice deficient in these molecules were transferred into NKT cell–deficient <italic>ApoE<sup>−/−</sup>Jα18<sup>−/−</sup></italic> mice. CD4<sup>+</sup> NKT cells deficient in IL-4, interferon-γ, or IL-21 augmented atherosclerosis in <italic>ApoE<sup>−/−</sup>Jα18<sup>−/−</sup></italic> mice by ≈95%, ≈80%, and ≈70%, respectively. Transfer of CD4<sup>+</sup> 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<sup>+</sup> NKT cells are twice as potent as CD4<sup>+</sup> T cells in promoting atherosclerosis.</p> </sec> <sec> <title> <underline>Conclusions:</underline> </title> <p>CD4<sup>+</sup> NKT cells potently promote atherosclerosis by perforin and granzyme B–dependent apoptosis that increases postapoptotic necrosis and inflammation.</p> </sec> </abstract>