David A Zidar1, Joseph C Mudd2, Steven Juchnowski2, Joao P Lopes2, Sara Sparks2, Samantha S Park2, Masakazu Ishikawa2, Robyn Osborne2, Jeffrey B Washam2, Cliburn Chan2, Nicholas T Funderburg2, Adeyinka Owoyele2, Mohamad A Alaiti2, Myttle Mayuga2, Carl Orringer2, Marco A Costa2, Daniel I Simon2, Curtis Tatsuoka2, Robert M Califf2, L Kristin Newby2, Michael M Lederman2, Kent J Weinhold2. 1. From the Harrington Heart and Vascular Institute, University Hospitals Case Medical Center, Case Western Reserve, University School of Medicine, Cleveland, OH (D.A.Z., S.J., J.P.L., M.I., M.A.A., M.M., M.A.C., D.I.S.); Division of Infectious Diseases, Department of Medicine (J.C.M., M.M.L.) and Department of Neurology (C.T.), Case Western Reserve University/University Hospitals of Cleveland, OH; Athersys, Inc., Cleveland, OH (S.S.P.); Department of Surgery (S.S., R.O., K.J.W.), Duke Heart Center (J.B.W.), and Department of Biostatistics and Bioinformatics (C.C.), and Duke Clinical Research Institute (R.M.C., L.K.N.), Duke University Medical Center, Durham, NC; Division of Medical Laboratory Science, School of Health and Rehabilitation Sciences, The Ohio State University, Columbus (N.T.F.); Case Western Reserve University School of Medicine, Cleveland, OH (A.O.); and Department of Medicine, University of Miami Health System, FL (C.O.). David.Zidar@UHhospitals.org. 2. From the Harrington Heart and Vascular Institute, University Hospitals Case Medical Center, Case Western Reserve, University School of Medicine, Cleveland, OH (D.A.Z., S.J., J.P.L., M.I., M.A.A., M.M., M.A.C., D.I.S.); Division of Infectious Diseases, Department of Medicine (J.C.M., M.M.L.) and Department of Neurology (C.T.), Case Western Reserve University/University Hospitals of Cleveland, OH; Athersys, Inc., Cleveland, OH (S.S.P.); Department of Surgery (S.S., R.O., K.J.W.), Duke Heart Center (J.B.W.), and Department of Biostatistics and Bioinformatics (C.C.), and Duke Clinical Research Institute (R.M.C., L.K.N.), Duke University Medical Center, Durham, NC; Division of Medical Laboratory Science, School of Health and Rehabilitation Sciences, The Ohio State University, Columbus (N.T.F.); Case Western Reserve University School of Medicine, Cleveland, OH (A.O.); and Department of Medicine, University of Miami Health System, FL (C.O.).
Abstract
OBJECTIVE: Inflammation in response to oxidized lipoproteins is thought to play a key role in acute coronary syndromes (ACS), but the pattern of immune activation has not been fully characterized. We sought to perform detailed phenotypic and functional analysis of CD8 T lymphocytes from patients presenting with ACS to determine activation patterns and potential immunologic correlates of ACS. APPROACH AND RESULTS: We used polychromatic flow cytometry to analyze the cytokine production profiles of naïve, effector, and memory CD8 T cells in patients with ACS compared with control subjects with stable coronary artery disease. ACS was associated with an altered distribution of circulating CD8(+) T-cell maturation subsets with reduced proportions of naïve cells and expansion of effector memory cells. ACS was also accompanied by impaired interleukin-2 production by phenotypically naïve CD8 T cells. These results were validated in a second replication cohort. Naïve CD8 cells from patients with ACS also had increased expression of programmed cell death-1, which correlated with interleukin-2 hypoproduction. In vitro, stimulation of CD8 T cells with oxidized low-density lipoprotein was sufficient to cause programmed cell death-1 upregulation and diminished interleukin-2 production by naïve CD8 T cells. CONCLUSIONS: In this exploratory analysis, naïve CD8(+) T cells from patients with ACS show phenotypic and functional characteristics of immune exhaustion: impaired interleukin-2 production and programmed cell death-1 upregulation. Exposure to oxidized low-density lipoprotein recapitulates these features in vitro. These data provide evidence that oxidized low-density lipoprotein could play a role in immune exhaustion, and this immunophenotype may be a biomarker for ACS.
OBJECTIVE:Inflammation in response to oxidized lipoproteins is thought to play a key role in acute coronary syndromes (ACS), but the pattern of immune activation has not been fully characterized. We sought to perform detailed phenotypic and functional analysis of CD8 T lymphocytes from patients presenting with ACS to determine activation patterns and potential immunologic correlates of ACS. APPROACH AND RESULTS: We used polychromatic flow cytometry to analyze the cytokine production profiles of naïve, effector, and memory CD8 T cells in patients with ACS compared with control subjects with stable coronary artery disease. ACS was associated with an altered distribution of circulating CD8(+) T-cell maturation subsets with reduced proportions of naïve cells and expansion of effector memory cells. ACS was also accompanied by impaired interleukin-2 production by phenotypically naïve CD8 T cells. These results were validated in a second replication cohort. Naïve CD8 cells from patients with ACS also had increased expression of programmed cell death-1, which correlated with interleukin-2 hypoproduction. In vitro, stimulation of CD8 T cells with oxidized low-density lipoprotein was sufficient to cause programmed cell death-1 upregulation and diminished interleukin-2 production by naïve CD8 T cells. CONCLUSIONS: In this exploratory analysis, naïve CD8(+) T cells from patients with ACS show phenotypic and functional characteristics of immune exhaustion: impaired interleukin-2 production and programmed cell death-1 upregulation. Exposure to oxidized low-density lipoprotein recapitulates these features in vitro. These data provide evidence that oxidized low-density lipoprotein could play a role in immune exhaustion, and this immunophenotype may be a biomarker for ACS.
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