{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,10]],"date-time":"2026-03-10T02:08:49Z","timestamp":1773108529572,"version":"3.50.1"},"reference-count":72,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"2","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation Research"],"published-print":{"date-parts":[[2015,1,16]]},"abstract":"<jats:sec>\n            <jats:title>\n              <jats:underline>Rationale:<\/jats:underline>\n            <\/jats:title>\n            <jats:p>\n              CD4\n              <jats:sup>+<\/jats:sup>\n              natural killer T (NKT) cells augment atherosclerosis in apolipoprotein E\u2013deficient (\n              <jats:italic>ApoE<\/jats:italic>\n              )\n              <jats:sup>\u2212\/\u2212<\/jats:sup>\n              mice but their mechanisms of action are unknown.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>\n              <jats:underline>Objectives:<\/jats:underline>\n            <\/jats:title>\n            <jats:p>\n              We investigated the roles of bystander T, B, and NK cells; NKT cell\u2013derived interferon-\u03b3, interleukin (IL)-4, and IL-21 cytokines; and NKT cell\u2013derived perforin and granzyme B cytotoxins in promoting CD4\n              <jats:sup>+<\/jats:sup>\n              NKT cell atherogenicity.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>\n              <jats:underline>Methods and Results:<\/jats:underline>\n            <\/jats:title>\n            <jats:p>\n              Transfer of CD4\n              <jats:sup>+<\/jats:sup>\n              NKT cells into T- and B-cell\u2013deficient\n              <jats:italic>\n                ApoE\n                <jats:sup>\u2212\/\u2212<\/jats:sup>\n                Rag2\n                <jats:sup>\u2212\/\u2212<\/jats:sup>\n              <\/jats:italic>\n              mice augmented aortic root atherosclerosis by \u224875% that was \u224830% of lesions in ApoE\n              <jats:sup>\u2212\/\u2212<\/jats:sup>\n              mice; macrophage accumulation similarly increased. Transferred NKT cells were identified in the liver and atherosclerotic lesions of recipient mice. Transfer of CD4\n              <jats:sup>+<\/jats:sup>\n              NKT cells into T-, B-cell\u2013deficient, and NK cell\u2013deficient\n              <jats:italic>\n                ApoE\n                <jats:sup>\u2212\/\u2212<\/jats:sup>\n                Rag2\n                <jats:sup>\u2212\/\u2212<\/jats:sup>\n                \u03b3C\n                <jats:sup>\u2212\/\u2212<\/jats:sup>\n              <\/jats:italic>\n              mice also augmented atherosclerosis. These data indicate that CD4\n              <jats:sup>+<\/jats:sup>\n              NKT cells can exert proatherogenic effects independent of other lymphocytes. To investigate the role of NKT cell\u2013derived interferon-\u03b3, IL-4, and IL-21 cytokines and perforin and granzyme B cytotoxins, CD4\n              <jats:sup>+<\/jats:sup>\n              NKT cells from mice deficient in these molecules were transferred into NKT cell\u2013deficient\n              <jats:italic>\n                ApoE\n                <jats:sup>\u2212\/\u2212<\/jats:sup>\n                J\u03b118\n                <jats:sup>\u2212\/\u2212<\/jats:sup>\n              <\/jats:italic>\n              mice. CD4\n              <jats:sup>+<\/jats:sup>\n              NKT cells deficient in IL-4, interferon-\u03b3, or IL-21 augmented atherosclerosis in\n              <jats:italic>\n                ApoE\n                <jats:sup>\u2212\/\u2212<\/jats:sup>\n                J\u03b118\n                <jats:sup>\u2212\/\u2212<\/jats:sup>\n              <\/jats:italic>\n              mice by \u224895%, \u224880%, and \u224870%, respectively. Transfer of CD4\n              <jats:sup>+<\/jats:sup>\n              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\n              <jats:sup>+<\/jats:sup>\n              NKT cells are twice as potent as CD4\n              <jats:sup>+<\/jats:sup>\n              T cells in promoting atherosclerosis.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>\n              <jats:underline>Conclusions:<\/jats:underline>\n            <\/jats:title>\n            <jats:p>\n              CD4\n              <jats:sup>+<\/jats:sup>\n              NKT cells potently promote atherosclerosis by perforin and granzyme B\u2013dependent apoptosis that increases postapoptotic necrosis and inflammation.\n            <\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/circresaha.116.304734","type":"journal-article","created":{"date-parts":[[2014,11,15]],"date-time":"2014-11-15T04:44:47Z","timestamp":1416026687000},"page":"245-254","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":55,"title":["CD4\n            <sup>+<\/sup>\n            Natural Killer T Cells Potently Augment Aortic Root Atherosclerosis by Perforin- and Granzyme B-Dependent Cytotoxicity"],"prefix":"10.1161","volume":"116","author":[{"given":"Yi","family":"Li","sequence":"first","affiliation":[{"name":"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 ..."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kelly","family":"To","sequence":"additional","affiliation":[{"name":"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 ..."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Peter","family":"Kanellakis","sequence":"additional","affiliation":[{"name":"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 ..."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hamid","family":"Hosseini","sequence":"additional","affiliation":[{"name":"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 ..."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Virginie","family":"Deswaerte","sequence":"additional","affiliation":[{"name":"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 ..."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Peter","family":"Tipping","sequence":"additional","affiliation":[{"name":"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 ..."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mark J.","family":"Smyth","sequence":"additional","affiliation":[{"name":"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 ..."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ban-Hock","family":"Toh","sequence":"additional","affiliation":[{"name":"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 ..."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alexander","family":"Bobik","sequence":"additional","affiliation":[{"name":"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 ..."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tin","family":"Kyaw","sequence":"additional","affiliation":[{"name":"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 ..."}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"276","reference":[{"key":"e_1_3_5_2_2","first-page":"251","article-title":"Evidence for apoptosis in advanced human atheroma. 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