CD4+ natural killer T cells potently augment aortic root atherosclerosis by perforin-and granzyme B-dependent cytotoxicity

Li, Yi, To, Kelly, Kanellakis, Peter, Hosseini, Hamid, Deswaerte, Virginie, Tipping, Peter, Smyth, Mark J., Toh, Ban-Hock, Bobik, Alexander and Kyaw, Tin (2015) CD4+ natural killer T cells potently augment aortic root atherosclerosis by perforin-and granzyme B-dependent cytotoxicity. Circulation Research, 116 2: 245-254. doi:10.1161/CIRCRESAHA.116.304734


Author Li, Yi
To, Kelly
Kanellakis, Peter
Hosseini, Hamid
Deswaerte, Virginie
Tipping, Peter
Smyth, Mark J.
Toh, Ban-Hock
Bobik, Alexander
Kyaw, Tin
Title CD4+ natural killer T cells potently augment aortic root atherosclerosis by perforin-and granzyme B-dependent cytotoxicity
Formatted title
CD4+ natural killer T cells potently augment aortic root atherosclerosis by perforin-and granzyme B-dependent cytotoxicity
Journal name Circulation Research   Check publisher's open access policy
ISSN 1524-4571
0009-7330
Publication date 2015-01-16
Year available 2014
Sub-type Article (original research)
DOI 10.1161/CIRCRESAHA.116.304734
Open Access Status
Volume 116
Issue 2
Start page 245
End page 254
Total pages 10
Place of publication Philadelphia PA, United States
Publisher Lippincott Williams & Wilkins
Collection year 2015
Language eng
Formatted abstract
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 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-cell–deficient, 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 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 ApoE−/−Jα18−/− mice. CD4+ NKT cells deficient in IL-4, interferon-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 (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.
Keyword Atherosclerosis
Cell death
Granzymes
Inflammation
Natural killer T cells
Perforin
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ
Additional Notes Published online ahead of print 14 Nov 2014

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2015 Collection
School of Medicine Publications
 
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