Altered Maturation Status and Possible Immune Exhaustion of CD8 T Lymphocytes in the Peripheral Blood of Patients Presenting With Acute Coronary Syndromes, Arteriosclerosis, Thrombosis and Vascular Biology, December 10, 2015. David A. Zidar, Joseph C. Mudd, Steven Juchnowski, Joao P. Lopes, Sara Sparks,Samantha S. Park, Masakazu Ishikawa, Robyn Osborne, Jeffrey B. Washam, Cliburn Chan, Nicholas T. Funderburg, Adeyinka Owoyele, Mohamad A. Alaiti, Myttle Mayuga, Carl Orringer, Marco A. Costa, Daniel I. Simon, Curtis Tatsuoka, Robert M. Califf, L. Kristin Newby, Michael M. Lederman, Kent J. Weinhold.
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., R.M.C., L.K.N.), 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, 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 University of Miami Health System, FL (C.O.).
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 the evidence that oxidized low-density lipoprotein could play a role in immune exhaustion, and that this immunophenotype may be a biomarker for ACS.