Circulation. 2002;105:570-575
doi: 10.1161/hc0502.103348
doi: 10.1161/hc0502.103348
(Circulation. 2002;105:570.)
© 2002 American Heart Association, Inc.
Clinical Investigation and Reports |
T-Cell–Mediated Lysis of Endothelial Cells in Acute Coronary Syndromes
From the Departments of Medicine (T.N., S.S., K.J.W., J.J.G., C.M.W.) and Immunology (K.J.W., J.J.G., C.M.W.) and Division of Cardiology (S.L.K., R.L.F.), Mayo Clinic, Rochester, Minn.
Correspondence Cornelia M. Weyand, MD, Mayo Clinic, 200 First St SW, Rochester, MN 55905. E-mail weyand.cornelia{at}mayo.edu
Background— CD4 T lymphocytes accumulate in unstable plaque. The direct and indirect involvement of these T cells in tissue injury and plaque instability is not understood.
Methods and Results— Gene profiling identified perforin, CD161, and members of the killer-cell immunoglobulin-like receptors as being differentially expressed in CD4+CD28null T cells, a T-cell subset that preferentially infiltrates unstable plaque. Frequencies of CD161+ and perforin-expressing CD4 T cells in peripheral blood were significantly increased in patients with unstable angina (UA). CD161 appeared on CD4+CD28null T cells after stimulation, suggesting spontaneous activation of circulating CD4 T cells in UA. Perforin-expressing CD4+ T-cell clones from patients with UA exhibited cytotoxic activity against human umbilical vein endothelial cells (HUVECs) in redirected cytotoxicity assays after T-cell receptor triggering and also after stimulation of major histocompatibility complex class I–recognizing killer-cell immunoglobulin-like receptors. HUVEC cytolysis was dependent on granule exocytosis, as demonstrated by the paralyzing effect of pretreating CD4+CD28null T cells with strontium. Incubation of HUVECs with C-reactive protein (CRP) increased HUVEC lysis in a dose-dependent fashion.
Conclusions— In patients with UA, CD4 T cells undergo a change in functional profile and acquire cytotoxic capability. Cytotoxic CD4 T cells effectively kill endothelial cells; CRP sensitizes endothelial cells to the cytotoxic process. We propose that T-cell–mediated endothelial cell injury is a novel pathway of tissue damage that contributes to plaque destabilization. The sensitizing effect of CRP suggests synergy between dysregulated T-cell function and acute phase proteins in acute coronary syndromes.
Key Words: apoptosis • endothelium • lymphocytes • coronary disease • plaque
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|
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|
|
|
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|
|
|
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|
|
|
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|
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|
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|
|
|
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|
|
|
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|
|
|
|
|
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|
|
|
|
 |
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
 |
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
 |
|
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|
|
|
|
 |
|
 T. Suzuki, K. Fukuo, T. Suhara, O. Yasuda, N. Sato, Y. Takemura, M. Tsubakimoto, and T. Ogihara Eicosapentaenoic Acid Protects Endothelial Cells Against Anoikis Through Restoration of cFLIP Hypertension, September 1, 2003; 42(3): 342 - 348. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Nakajima, O. Goek, X. Zhang, S. L. Kopecky, R. L. Frye, J. J. Goronzy, and C. M. Weyand De Novo Expression of Killer Immunoglobulin-Like Receptors and Signaling Proteins Regulates the Cytotoxic Function of CD4 T Cells in Acute Coronary Syndromes Circ. Res., July 25, 2003; 93(2): 106 - 113. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. M. Bashore and T. Gehrig Cholesterol emboli after invasive cardiac procedures J. Am. Coll. Cardiol., July 16, 2003; 42(2): 217 - 218. [Full Text] [PDF]
|
|
|
|
|
|
E. R. Sherwood, C. Y. Lin, W. Tao, C. A. Hartmann, J. E. Dujon, A. J. French, and T. K. Varma {beta}2 Microglobulin Knockout Mice Are Resistant to Lethal Intraabdominal Sepsis Am. J. Respir. Crit. Care Med., June 15, 2003; 167(12): 1641 - 1649. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 W. Koenig C-reactive protein and cardiovascular risk: an update on what is going on in cardiology Nephrol. Dial. Transplant., June 1, 2003; 18(6): 1039 - 1041. [Full Text] [PDF]
|
|
|
|
|
|
H. Soejima, A. Irie, S. Miyamoto, I. Kajiwara, S. Kojima, J. Hokamaki, T. Sakamoto, T. Tanaka, M. Yoshimura, Y. Nishimura, et al. Preference Toward a T-Helper Type 1 Response in Patients With Coronary Spastic Angina Circulation, May 6, 2003; 107(17): 2196 - 2200. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
M. Valgimigli, L. Agnoletti, S. Curello, L. Comini, G. Francolini, F. Mastrorilli, E. Merli, R. Pirani, G. Guardigli, P. G. Grigolato, et al. Serum From Patients With Acute Coronary Syndromes Displays a Proapoptotic Effect on Human Endothelial Cells: A Possible Link to Pan-Coronary Syndromes Circulation, January 21, 2003; 107(2): 264 - 270. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. L. Bhatt, E. J. Topol, I. Kushner, and A. Sehgal The Arterial Inflammation Hypothesis Arch Intern Med, October 28, 2002; 162(19): 2249 - 2251. [Full Text] [PDF]
|
|
|
|
|
|
D. L. Bhatt and E. J. Topol Need to Test the Arterial Inflammation Hypothesis Circulation, July 2, 2002; 106(1): 136 - 140. [Full Text] [PDF]
|
|