Cytotoxic and proinflammatory CD8+ T lymphocytes promote development of vulnerable atherosclerotic plaques in ApoE-deficient mice

Tin Kyaw, Amy Winship, Christopher Tay, Peter Kanellakis, Hamid Hosseini, Anh Cao, Priscilla Li, Peter Tipping, Alex Bobik, Ban-Hock Toh

Research output: Contribution to journalArticleResearchpeer-review

105 Citations (Scopus)

Abstract

Background—Heart attacks and strokes, leading causes of deaths globally, arise from thrombotic occlusion of ruptured vulnerable atherosclerotic plaques characterized by abundant apoptosis, large necrotic cores derived from inefficient apoptotic cell clearance, thin fibrous caps, and focal inflammation. The genesis of apoptosis and necrotic cores in these vulnerable atherosclerotic plaques remains unknown. Cytotoxic CD8+ T lymphocytes represent up to 50% of leukocytes in advanced human plaques and dominate early immune responses in mouse lesions, yet their role in atherosclerosis also remains unresolved. Methods and Results—CD8+ T-lymphocyte depletion by CD8α or CD8β monoclonal antibody in apolipoprotein E-deficient mice fed a high-fat diet ameliorated atherosclerosis by reducing lipid and macrophage accumulation, apoptosis, necrotic cores, and monocyte chemoattractant protein 1, interleukin 1β, interferon γ, and vascular cell adhesion molecule 1. Transfer of CD8+ T cells into lymphocyte-deficient, apolipoprotein E-deficient mice partially reconstituted CD8+ T cells in lymphoid compartments and was associated with CD8+ T-cell infiltration in lesions, increased lipid and macrophage accumulation, apoptotic cells, necrotic cores, and interleukin 1β in atherosclerotic lesions. Transfer of CD8+ T cells deficient in perforin, granzyme B, or tumor necrosis factor α but not interferon γ failed to increase atherosclerotic lesions despite partial reconstitution in the lymphoid system and the presence in atherosclerotic lesions. Macrophages, smooth muscle cells, and endothelial cells were identified as apoptotic targets. Conclusions—We conclude that CD8+ T lymphocytes promote the development of vulnerable atherosclerotic plaques by perforin- and granzyme B–mediated apoptosis of macrophages, smooth muscle cells, and endothelial cells that, in turn, leads to necrotic core formation and further augments inflammation by tumor necrosis factor α secretion.
Original languageEnglish
Pages (from-to)1028 - 1039
Number of pages12
JournalCirculation
Volume127
Issue number9
DOIs
Publication statusPublished - 5 Mar 2013

Keywords

  • CD8+ T cells
  • perforin
  • granzyme B
  • vulnerable atherosclerotic plaque

Cite this

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title = "Cytotoxic and proinflammatory CD8+ T lymphocytes promote development of vulnerable atherosclerotic plaques in ApoE-deficient mice",
abstract = "Background—Heart attacks and strokes, leading causes of deaths globally, arise from thrombotic occlusion of ruptured vulnerable atherosclerotic plaques characterized by abundant apoptosis, large necrotic cores derived from inefficient apoptotic cell clearance, thin fibrous caps, and focal inflammation. The genesis of apoptosis and necrotic cores in these vulnerable atherosclerotic plaques remains unknown. Cytotoxic CD8+ T lymphocytes represent up to 50{\%} of leukocytes in advanced human plaques and dominate early immune responses in mouse lesions, yet their role in atherosclerosis also remains unresolved. Methods and Results—CD8+ T-lymphocyte depletion by CD8α or CD8β monoclonal antibody in apolipoprotein E-deficient mice fed a high-fat diet ameliorated atherosclerosis by reducing lipid and macrophage accumulation, apoptosis, necrotic cores, and monocyte chemoattractant protein 1, interleukin 1β, interferon γ, and vascular cell adhesion molecule 1. Transfer of CD8+ T cells into lymphocyte-deficient, apolipoprotein E-deficient mice partially reconstituted CD8+ T cells in lymphoid compartments and was associated with CD8+ T-cell infiltration in lesions, increased lipid and macrophage accumulation, apoptotic cells, necrotic cores, and interleukin 1β in atherosclerotic lesions. Transfer of CD8+ T cells deficient in perforin, granzyme B, or tumor necrosis factor α but not interferon γ failed to increase atherosclerotic lesions despite partial reconstitution in the lymphoid system and the presence in atherosclerotic lesions. Macrophages, smooth muscle cells, and endothelial cells were identified as apoptotic targets. Conclusions—We conclude that CD8+ T lymphocytes promote the development of vulnerable atherosclerotic plaques by perforin- and granzyme B–mediated apoptosis of macrophages, smooth muscle cells, and endothelial cells that, in turn, leads to necrotic core formation and further augments inflammation by tumor necrosis factor α secretion.",
keywords = "CD8+ T cells, perforin, granzyme B, vulnerable atherosclerotic plaque",
author = "Tin Kyaw and Amy Winship and Christopher Tay and Peter Kanellakis and Hamid Hosseini and Anh Cao and Priscilla Li and Peter Tipping and Alex Bobik and Ban-Hock Toh",
year = "2013",
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language = "English",
volume = "127",
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Cytotoxic and proinflammatory CD8+ T lymphocytes promote development of vulnerable atherosclerotic plaques in ApoE-deficient mice. / Kyaw, Tin; Winship, Amy; Tay, Christopher; Kanellakis, Peter; Hosseini, Hamid; Cao, Anh; Li, Priscilla; Tipping, Peter; Bobik, Alex; Toh, Ban-Hock.

In: Circulation, Vol. 127, No. 9, 05.03.2013, p. 1028 - 1039.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Cytotoxic and proinflammatory CD8+ T lymphocytes promote development of vulnerable atherosclerotic plaques in ApoE-deficient mice

AU - Kyaw, Tin

AU - Winship, Amy

AU - Tay, Christopher

AU - Kanellakis, Peter

AU - Hosseini, Hamid

AU - Cao, Anh

AU - Li, Priscilla

AU - Tipping, Peter

AU - Bobik, Alex

AU - Toh, Ban-Hock

PY - 2013/3/5

Y1 - 2013/3/5

N2 - Background—Heart attacks and strokes, leading causes of deaths globally, arise from thrombotic occlusion of ruptured vulnerable atherosclerotic plaques characterized by abundant apoptosis, large necrotic cores derived from inefficient apoptotic cell clearance, thin fibrous caps, and focal inflammation. The genesis of apoptosis and necrotic cores in these vulnerable atherosclerotic plaques remains unknown. Cytotoxic CD8+ T lymphocytes represent up to 50% of leukocytes in advanced human plaques and dominate early immune responses in mouse lesions, yet their role in atherosclerosis also remains unresolved. Methods and Results—CD8+ T-lymphocyte depletion by CD8α or CD8β monoclonal antibody in apolipoprotein E-deficient mice fed a high-fat diet ameliorated atherosclerosis by reducing lipid and macrophage accumulation, apoptosis, necrotic cores, and monocyte chemoattractant protein 1, interleukin 1β, interferon γ, and vascular cell adhesion molecule 1. Transfer of CD8+ T cells into lymphocyte-deficient, apolipoprotein E-deficient mice partially reconstituted CD8+ T cells in lymphoid compartments and was associated with CD8+ T-cell infiltration in lesions, increased lipid and macrophage accumulation, apoptotic cells, necrotic cores, and interleukin 1β in atherosclerotic lesions. Transfer of CD8+ T cells deficient in perforin, granzyme B, or tumor necrosis factor α but not interferon γ failed to increase atherosclerotic lesions despite partial reconstitution in the lymphoid system and the presence in atherosclerotic lesions. Macrophages, smooth muscle cells, and endothelial cells were identified as apoptotic targets. Conclusions—We conclude that CD8+ T lymphocytes promote the development of vulnerable atherosclerotic plaques by perforin- and granzyme B–mediated apoptosis of macrophages, smooth muscle cells, and endothelial cells that, in turn, leads to necrotic core formation and further augments inflammation by tumor necrosis factor α secretion.

AB - Background—Heart attacks and strokes, leading causes of deaths globally, arise from thrombotic occlusion of ruptured vulnerable atherosclerotic plaques characterized by abundant apoptosis, large necrotic cores derived from inefficient apoptotic cell clearance, thin fibrous caps, and focal inflammation. The genesis of apoptosis and necrotic cores in these vulnerable atherosclerotic plaques remains unknown. Cytotoxic CD8+ T lymphocytes represent up to 50% of leukocytes in advanced human plaques and dominate early immune responses in mouse lesions, yet their role in atherosclerosis also remains unresolved. Methods and Results—CD8+ T-lymphocyte depletion by CD8α or CD8β monoclonal antibody in apolipoprotein E-deficient mice fed a high-fat diet ameliorated atherosclerosis by reducing lipid and macrophage accumulation, apoptosis, necrotic cores, and monocyte chemoattractant protein 1, interleukin 1β, interferon γ, and vascular cell adhesion molecule 1. Transfer of CD8+ T cells into lymphocyte-deficient, apolipoprotein E-deficient mice partially reconstituted CD8+ T cells in lymphoid compartments and was associated with CD8+ T-cell infiltration in lesions, increased lipid and macrophage accumulation, apoptotic cells, necrotic cores, and interleukin 1β in atherosclerotic lesions. Transfer of CD8+ T cells deficient in perforin, granzyme B, or tumor necrosis factor α but not interferon γ failed to increase atherosclerotic lesions despite partial reconstitution in the lymphoid system and the presence in atherosclerotic lesions. Macrophages, smooth muscle cells, and endothelial cells were identified as apoptotic targets. Conclusions—We conclude that CD8+ T lymphocytes promote the development of vulnerable atherosclerotic plaques by perforin- and granzyme B–mediated apoptosis of macrophages, smooth muscle cells, and endothelial cells that, in turn, leads to necrotic core formation and further augments inflammation by tumor necrosis factor α secretion.

KW - CD8+ T cells

KW - perforin

KW - granzyme B

KW - vulnerable atherosclerotic plaque

UR - http://www.ncbi.nlm.nih.gov/pubmed/23395974

U2 - 10.1161/CIRCULATIONAHA.112.001347

DO - 10.1161/CIRCULATIONAHA.112.001347

M3 - Article

VL - 127

SP - 1028

EP - 1039

JO - Circulation

JF - Circulation

SN - 0009-7322

IS - 9

ER -