PMID- 25398236 OWN - NLM STAT- MEDLINE DCOM- 20150320 LR - 20220310 IS - 1524-4571 (Electronic) IS - 0009-7330 (Linking) VI - 116 IP - 2 DP - 2015 Jan 16 TI - CD4+ natural killer T cells potently augment aortic root atherosclerosis by perforin- and granzyme B-dependent cytotoxicity. PG - 245-54 LID - 10.1161/CIRCRESAHA.116.304734 [doi] 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. CI - (c) 2014 American Heart Association, Inc. FAU - Li, Yi AU - Li Y AD - From the BakerIDI Heart and Diabetes Institute, Melbourne, Australia (L.Y., K.T., P.K., H.H., V.D., A.B., T.K.); Department of Medicine, Centre for Inflammatory Diseases, Southern Clinical School (L.Y., K.T., P.T., B.-H.T., T.K.) and Department of Immunology, Central Clinical School, Faculty of Medicine Nursing and Health Sciences (A.B.), Monash University, Melbourne, Australia; Immunology in Cancer and Infection Laboratory, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia (M.J.S.); and School of Medicine, University of Queensland, Herston, Queensland, Australia (M.J.S.). FAU - To, Kelly AU - To K AD - From the BakerIDI Heart and Diabetes Institute, Melbourne, Australia (L.Y., K.T., P.K., H.H., V.D., A.B., T.K.); Department of Medicine, Centre for Inflammatory Diseases, Southern Clinical School (L.Y., K.T., P.T., B.-H.T., T.K.) and Department of Immunology, Central Clinical School, Faculty of Medicine Nursing and Health Sciences (A.B.), Monash University, Melbourne, Australia; Immunology in Cancer and Infection Laboratory, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia (M.J.S.); and School of Medicine, University of Queensland, Herston, Queensland, Australia (M.J.S.). FAU - Kanellakis, Peter AU - Kanellakis P AD - From the BakerIDI Heart and Diabetes Institute, Melbourne, Australia (L.Y., K.T., P.K., H.H., V.D., A.B., T.K.); Department of Medicine, Centre for Inflammatory Diseases, Southern Clinical School (L.Y., K.T., P.T., B.-H.T., T.K.) and Department of Immunology, Central Clinical School, Faculty of Medicine Nursing and Health Sciences (A.B.), Monash University, Melbourne, Australia; Immunology in Cancer and Infection Laboratory, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia (M.J.S.); and School of Medicine, University of Queensland, Herston, Queensland, Australia (M.J.S.). FAU - Hosseini, Hamid AU - Hosseini H AD - From the BakerIDI Heart and Diabetes Institute, Melbourne, Australia (L.Y., K.T., P.K., H.H., V.D., A.B., T.K.); Department of Medicine, Centre for Inflammatory Diseases, Southern Clinical School (L.Y., K.T., P.T., B.-H.T., T.K.) and Department of Immunology, Central Clinical School, Faculty of Medicine Nursing and Health Sciences (A.B.), Monash University, Melbourne, Australia; Immunology in Cancer and Infection Laboratory, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia (M.J.S.); and School of Medicine, University of Queensland, Herston, Queensland, Australia (M.J.S.). FAU - Deswaerte, Virginie AU - Deswaerte V AD - From the BakerIDI Heart and Diabetes Institute, Melbourne, Australia (L.Y., K.T., P.K., H.H., V.D., A.B., T.K.); Department of Medicine, Centre for Inflammatory Diseases, Southern Clinical School (L.Y., K.T., P.T., B.-H.T., T.K.) and Department of Immunology, Central Clinical School, Faculty of Medicine Nursing and Health Sciences (A.B.), Monash University, Melbourne, Australia; Immunology in Cancer and Infection Laboratory, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia (M.J.S.); and School of Medicine, University of Queensland, Herston, Queensland, Australia (M.J.S.). FAU - Tipping, Peter AU - Tipping P AD - From the BakerIDI Heart and Diabetes Institute, Melbourne, Australia (L.Y., K.T., P.K., H.H., V.D., A.B., T.K.); Department of Medicine, Centre for Inflammatory Diseases, Southern Clinical School (L.Y., K.T., P.T., B.-H.T., T.K.) and Department of Immunology, Central Clinical School, Faculty of Medicine Nursing and Health Sciences (A.B.), Monash University, Melbourne, Australia; Immunology in Cancer and Infection Laboratory, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia (M.J.S.); and School of Medicine, University of Queensland, Herston, Queensland, Australia (M.J.S.). FAU - Smyth, Mark J AU - Smyth MJ AD - From the BakerIDI Heart and Diabetes Institute, Melbourne, Australia (L.Y., K.T., P.K., H.H., V.D., A.B., T.K.); Department of Medicine, Centre for Inflammatory Diseases, Southern Clinical School (L.Y., K.T., P.T., B.-H.T., T.K.) and Department of Immunology, Central Clinical School, Faculty of Medicine Nursing and Health Sciences (A.B.), Monash University, Melbourne, Australia; Immunology in Cancer and Infection Laboratory, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia (M.J.S.); and School of Medicine, University of Queensland, Herston, Queensland, Australia (M.J.S.). FAU - Toh, Ban-Hock AU - Toh BH AD - From the BakerIDI Heart and Diabetes Institute, Melbourne, Australia (L.Y., K.T., P.K., H.H., V.D., A.B., T.K.); Department of Medicine, Centre for Inflammatory Diseases, Southern Clinical School (L.Y., K.T., P.T., B.-H.T., T.K.) and Department of Immunology, Central Clinical School, Faculty of Medicine Nursing and Health Sciences (A.B.), Monash University, Melbourne, Australia; Immunology in Cancer and Infection Laboratory, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia (M.J.S.); and School of Medicine, University of Queensland, Herston, Queensland, Australia (M.J.S.). FAU - Bobik, Alexander AU - Bobik A AD - From the BakerIDI Heart and Diabetes Institute, Melbourne, Australia (L.Y., K.T., P.K., H.H., V.D., A.B., T.K.); Department of Medicine, Centre for Inflammatory Diseases, Southern Clinical School (L.Y., K.T., P.T., B.-H.T., T.K.) and Department of Immunology, Central Clinical School, Faculty of Medicine Nursing and Health Sciences (A.B.), Monash University, Melbourne, Australia; Immunology in Cancer and Infection Laboratory, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia (M.J.S.); and School of Medicine, University of Queensland, Herston, Queensland, Australia (M.J.S.). FAU - Kyaw, Tin AU - Kyaw T AD - From the BakerIDI Heart and Diabetes Institute, Melbourne, Australia (L.Y., K.T., P.K., H.H., V.D., A.B., T.K.); Department of Medicine, Centre for Inflammatory Diseases, Southern Clinical School (L.Y., K.T., P.T., B.-H.T., T.K.) and Department of Immunology, Central Clinical School, Faculty of Medicine Nursing and Health Sciences (A.B.), Monash University, Melbourne, Australia; Immunology in Cancer and Infection Laboratory, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia (M.J.S.); and School of Medicine, University of Queensland, Herston, Queensland, Australia (M.J.S.). tinsoe.kyaw@bakeridi.edu.au. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20141114 PL - United States TA - Circ Res JT - Circulation research JID - 0047103 RN - 0 (Pore Forming Cytotoxic Proteins) RN - 0 (perforin, mouse) RN - EC 3.4.21.- (Granzymes) RN - EC 3.4.21.- (Gzmb protein, mouse) SB - IM MH - Adoptive Transfer/methods MH - Animals MH - Atherosclerosis/immunology/*metabolism/pathology MH - CD4-Positive T-Lymphocytes/immunology/*metabolism MH - Granzymes/*deficiency MH - Male MH - Mice MH - Mice, Knockout MH - Natural Killer T-Cells/immunology/*metabolism MH - Pore Forming Cytotoxic Proteins/*deficiency MH - Sinus of Valsalva/immunology/*metabolism/pathology OTO - NOTNLM OT - atherosclerosis OT - cell death OT - granzymes OT - inflammation OT - natural killer T cells OT - perforin EDAT- 2014/11/16 06:00 MHDA- 2015/03/21 06:00 CRDT- 2014/11/16 06:00 PHST- 2014/11/16 06:00 [entrez] PHST- 2014/11/16 06:00 [pubmed] PHST- 2015/03/21 06:00 [medline] AID - CIRCRESAHA.116.304734 [pii] AID - 10.1161/CIRCRESAHA.116.304734 [doi] PST - ppublish SO - Circ Res. 2015 Jan 16;116(2):245-54. doi: 10.1161/CIRCRESAHA.116.304734. Epub 2014 Nov 14.