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.
  
  
  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.
authors: Vascular Biology and Atherosclerosis Laboratory, Baker IDI Heart and Diabetes Institute, Victoria, Australia. tinsoe.kyaw@bakeridi.edu.au
authors: Tin
authors: T
authors: Kyaw
authors: Amy
authors: A
authors: Winship
authors: Christopher
authors: C
authors: Tay
authors: Peter
authors: P
authors: Kanellakis
authors: Hamid
authors: H
authors: Hosseini
authors: Anh
authors: A
authors: Cao
authors: Priscilla
authors: P
authors: Li
authors: Peter
authors: P
authors: Tipping
authors: Alex
authors: A
authors: Bobik
authors: Ban-Hock
authors: BH
authors: Toh
mesh_terms: D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D059305:Diet, High-Fat / Q000009:adverse effects; D007249:Inflammation / Q000235:genetics / Q000276:immunology / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D058226:Plaque, Atherosclerotic / Q000235:genetics / Q000276:immunology* / Q000473:pathology*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*
chemical_list: D001057:Apolipoproteins E