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

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.

• Authors: Yi Li, Kelly To, Peter Kanellakis, Hamid Hosseini, Virginie Deswaerte, Peter Tipping, Mark J Smyth, Ban-Hock Toh, Alexander Bobik, Tin Kyaw
• Journal: Circulation research (Circ Res) Vol. 116 Issue 2 Pg. 245-54 (Jan 16 2015) ISSN: 1524-4571 [Electronic] United States
• PMID: 25398236 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2014 American Heart Association, Inc.

Chemical References

• Pore Forming Cytotoxic Proteins
• perforin, mouse
• Granzymes
• Gzmb protein, mouse

Topics

• Adoptive Transfer (methods)
• Animals
• Atherosclerosis (immunology, metabolism, pathology)
• CD4-Positive T-Lymphocytes (immunology, metabolism)
• Granzymes (deficiency)
• Male
• Mice
• Mice, Knockout
• Natural Killer T-Cells (immunology, metabolism)
• Pore Forming Cytotoxic Proteins (deficiency)
• Sinus of Valsalva (immunology, metabolism, pathology)