Altered Maturation Status and Possible Immune Exhaustion of CD8 T Lymphocytes in the Peripheral Blood of Patients Presenting with Acute Coronary Syndromes

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 Edward Orringer, Marco A. Costa, Daniel I. Simon, Curtis Tatsuoka, Robert M. Califf, L. Kristin NewbyMichael M. Lederman, Kent J. Weinhold

Research output: Contribution to journalArticle

3 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)389-397
Number of pages9
JournalArteriosclerosis, Thrombosis, and Vascular Biology
Volume36
Issue number2
DOIs
StatePublished - Feb 1 2016

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Acute Coronary Syndrome
T-Lymphocytes
Interleukin-2
Cell Death
Up-Regulation
T-Lymphocyte Subsets
Lipoproteins
Coronary Artery Disease
Flow Cytometry
Biomarkers
Cytokines
Inflammation

Keywords

  • acute coronary syndrome
  • inflammation
  • interleukins
  • oxidized low density lipoprotein
  • programmed cell death, type 1

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Cite this

Altered Maturation Status and Possible Immune Exhaustion of CD8 T Lymphocytes in the Peripheral Blood of Patients Presenting with Acute Coronary Syndromes. / Zidar, David A.; Mudd, Joseph C.; Juchnowski, Steven; Lopes, Joao P.; Sparks, Sara; Park, Samantha S.; Ishikawa, Masakazu; Osborne, Robyn; Washam, Jeffrey B.; Chan, Cliburn; Funderburg, Nicholas T.; Owoyele, Adeyinka; Alaiti, Mohamad A.; Mayuga, Myttle; Orringer, Carl Edward; Costa, Marco A.; Simon, Daniel I.; Tatsuoka, Curtis; Califf, Robert M.; Kristin Newby, L.; Lederman, Michael M.; Weinhold, Kent J.

In: Arteriosclerosis, Thrombosis, and Vascular Biology, Vol. 36, No. 2, 01.02.2016, p. 389-397.

Research output: Contribution to journalArticle

Zidar, DA, Mudd, JC, Juchnowski, S, Lopes, JP, Sparks, S, Park, SS, Ishikawa, M, Osborne, R, Washam, JB, Chan, C, Funderburg, NT, Owoyele, A, Alaiti, MA, Mayuga, M, Orringer, CE, Costa, MA, Simon, DI, Tatsuoka, C, Califf, RM, Kristin Newby, L, Lederman, MM & Weinhold, KJ 2016, '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, vol. 36, no. 2, pp. 389-397. https://doi.org/10.1161/ATVBAHA.115.306112
Zidar, David A. ; Mudd, Joseph C. ; Juchnowski, Steven ; Lopes, Joao P. ; Sparks, Sara ; Park, Samantha S. ; Ishikawa, Masakazu ; Osborne, Robyn ; Washam, Jeffrey B. ; Chan, Cliburn ; Funderburg, Nicholas T. ; Owoyele, Adeyinka ; Alaiti, Mohamad A. ; Mayuga, Myttle ; Orringer, Carl Edward ; Costa, Marco A. ; Simon, Daniel I. ; Tatsuoka, Curtis ; Califf, Robert M. ; Kristin Newby, L. ; Lederman, Michael M. ; Weinhold, Kent J. / Altered Maturation Status and Possible Immune Exhaustion of CD8 T Lymphocytes in the Peripheral Blood of Patients Presenting with Acute Coronary Syndromes. In: Arteriosclerosis, Thrombosis, and Vascular Biology. 2016 ; Vol. 36, No. 2. pp. 389-397.
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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 na{\"i}ve, 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 na{\"i}ve cells and expansion of effector memory cells. ACS was also accompanied by impaired interleukin-2 production by phenotypically na{\"i}ve CD8 T cells. These results were validated in a second replication cohort. Na{\"i}ve 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 na{\"i}ve CD8 T cells. Conclusions-In this exploratory analysis, na{\"i}ve 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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AU - Zidar, David A.

AU - Mudd, Joseph C.

AU - Juchnowski, Steven

AU - Lopes, Joao P.

AU - Sparks, Sara

AU - Park, Samantha S.

AU - Ishikawa, Masakazu

AU - Osborne, Robyn

AU - Washam, Jeffrey B.

AU - Chan, Cliburn

AU - Funderburg, Nicholas T.

AU - Owoyele, Adeyinka

AU - Alaiti, Mohamad A.

AU - Mayuga, Myttle

AU - Orringer, Carl Edward

AU - Costa, Marco A.

AU - Simon, Daniel I.

AU - Tatsuoka, Curtis

AU - Califf, Robert M.

AU - Kristin Newby, L.

AU - Lederman, Michael M.

AU - Weinhold, Kent J.

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N2 - 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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KW - programmed cell death, type 1

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