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

Yi Li, Kelly To, Peter Kanellakis, Hamid Hosseini, Virginie Deswaerte, Peter George Tipping, Mark J Smyth, Ban-Hock Toh, Alexander Bobik, Tin Soe Kyaw

Research output: Contribution to journalArticleResearchpeer-review

27 Citations (Scopus)

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-gamma, 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 approximately 75 that was approximately 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(-/-)gammaC(-/-) 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-gamma, 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(-/-)Jalpha18(-/-) mice. CD4(+) NKT cells deficient in IL-4, interferon-gamma, or IL-21 augmented atherosclerosis in ApoE(-/-)Jalpha18(-/-) mice by approximately 95 , approximately 80 , and approximately 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.
Original languageEnglish
Pages (from-to)245 - 254
Number of pages10
JournalCirculation Research
Volume116
Issue number2
DOIs
Publication statusPublished - 2015

Cite this

@article{82d38a21e1f643a48a3a11ac695dd88e,
title = "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-gamma, 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 approximately 75 that was approximately 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(-/-)gammaC(-/-) 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-gamma, 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(-/-)Jalpha18(-/-) mice. CD4(+) NKT cells deficient in IL-4, interferon-gamma, or IL-21 augmented atherosclerosis in ApoE(-/-)Jalpha18(-/-) mice by approximately 95 , approximately 80 , and approximately 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.",
author = "Yi Li and Kelly To and Peter Kanellakis and Hamid Hosseini and Virginie Deswaerte and Tipping, {Peter George} and Smyth, {Mark J} and Ban-Hock Toh and Alexander Bobik and Kyaw, {Tin Soe}",
year = "2015",
doi = "10.1161/CIRCRESAHA.116.304734",
language = "English",
volume = "116",
pages = "245 -- 254",
journal = "Circulation Research",
issn = "0009-7330",
publisher = "Lippincott Williams & Wilkins",
number = "2",

}

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 George; Smyth, Mark J; Toh, Ban-Hock; Bobik, Alexander; Kyaw, Tin Soe.

In: Circulation Research, Vol. 116, No. 2, 2015, p. 245 - 254.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - CD4+ natural killer T cells potently augment aortic root atherosclerosis by perforin- and granzyme B-dependent cytotoxicity

AU - Li, Yi

AU - To, Kelly

AU - Kanellakis, Peter

AU - Hosseini, Hamid

AU - Deswaerte, Virginie

AU - Tipping, Peter George

AU - Smyth, Mark J

AU - Toh, Ban-Hock

AU - Bobik, Alexander

AU - Kyaw, Tin Soe

PY - 2015

Y1 - 2015

N2 - 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-gamma, 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 approximately 75 that was approximately 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(-/-)gammaC(-/-) 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-gamma, 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(-/-)Jalpha18(-/-) mice. CD4(+) NKT cells deficient in IL-4, interferon-gamma, or IL-21 augmented atherosclerosis in ApoE(-/-)Jalpha18(-/-) mice by approximately 95 , approximately 80 , and approximately 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.

AB - 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-gamma, 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 approximately 75 that was approximately 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(-/-)gammaC(-/-) 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-gamma, 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(-/-)Jalpha18(-/-) mice. CD4(+) NKT cells deficient in IL-4, interferon-gamma, or IL-21 augmented atherosclerosis in ApoE(-/-)Jalpha18(-/-) mice by approximately 95 , approximately 80 , and approximately 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.

UR - http://circres.ahajournals.org/content/116/2/245.full.pdf+html

U2 - 10.1161/CIRCRESAHA.116.304734

DO - 10.1161/CIRCRESAHA.116.304734

M3 - Article

VL - 116

SP - 245

EP - 254

JO - Circulation Research

JF - Circulation Research

SN - 0009-7330

IS - 2

ER -