Abstract
T cell-mediated immunity plays a significant role in the development of atherosclerosis (AS). There is increasing evidence that CD8+ T cells are also involved in AS but their exact roles remain unclear. The inhibitory receptors programmed cell death-1 (PD-1) and T cell immunoglobulin and mucin domain 3 (Tim-3) are well known inhibitory molecules that play a crucial role in regulating CD8+ T cell activation or tolerance. Here, we demonstrate that the co-expression of PD-1 and Tim-3 on CD8+ T cells is up-regulated in AS patients. PD-1+ Tim-3+ CD8+ T cells are enriched for within the central T (TCM) cell subset, with high proliferative activity and CD127 expression. Co-expression of PD-1 and Tim-3 on CD8+ T cells is associated with increased anti-atherogenic cytokine production as well as decreased pro-atherogenic cytokine production. Blockade of PD-1 and Tim-3 results in a decrease of anti-atherogenic cytokine production by PD-1+ Tim-3+ CD8+ T cells and in an augmentation of TNF-α and IFN-γ production. These findings highlight the important role of the PD-1 and Tim-3 pathways in regulating CD8+ T cells function in human AS.
Publication types
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Comparative Study
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Research Support, Non-U.S. Gov't
MeSH terms
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Aged
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Aged, 80 and over
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Animals
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Atherosclerosis / immunology*
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Atherosclerosis / metabolism
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Atherosclerosis / pathology
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CD8-Positive T-Lymphocytes / immunology*
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CD8-Positive T-Lymphocytes / metabolism
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CD8-Positive T-Lymphocytes / pathology
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Case-Control Studies
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Cell Proliferation
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Cells, Cultured
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Female
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Flow Cytometry
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Hepatitis A Virus Cellular Receptor 2
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Humans
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Immune Tolerance
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Immunity, Cellular / immunology*
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Immunoenzyme Techniques
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Lymphocyte Activation / immunology*
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Lymphocytes / immunology*
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Lymphocytes / metabolism
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Lymphocytes / pathology
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Male
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Membrane Proteins / metabolism*
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Mice
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Middle Aged
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Programmed Cell Death 1 Receptor / metabolism*
Substances
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HAVCR2 protein, human
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Hepatitis A Virus Cellular Receptor 2
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Membrane Proteins
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PDCD1 protein, human
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Programmed Cell Death 1 Receptor
Grants and funding
This work was supported by National Natural Science Foundation of China (grant no. 81272747), the Science and Technology Commission foundation of Shanghai, China (no. 13140903802), and the Medicine and Engineering Cross foundation of Shanghai Jiaotong University (no. YG2012MS33). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.