title: T-cell-mediated lysis of endothelial cells in acute coronary syndromes.
abstract: BACKGROUND
  CD4 T lymphocytes accumulate in unstable plaque. The direct and indirect involvement of these T cells in tissue injury and plaque instability is not understood.
  
  
  RESULTS
  Gene profiling identified perforin, CD161, and members of the killer-cell immunoglobulin-like receptors as being differentially expressed in CD4(+)CD28(null) T cells, a T-cell subset that preferentially infiltrates unstable plaque. Frequencies of CD161(+) and perforin-expressing CD4 T cells in peripheral blood were significantly increased in patients with unstable angina (UA). CD161 appeared on CD4(+)CD28(null) T cells after stimulation, suggesting spontaneous activation of circulating CD4 T cells in UA. Perforin-expressing CD4(+) T-cell clones from patients with UA exhibited cytotoxic activity against human umbilical vein endothelial cells (HUVECs) in redirected cytotoxicity assays after T-cell receptor triggering and also after stimulation of major histocompatibility complex class I-recognizing killer-cell immunoglobulin-like receptors. HUVEC cytolysis was dependent on granule exocytosis, as demonstrated by the paralyzing effect of pretreating CD4(+)CD28(null) T cells with strontium. Incubation of HUVECs with C-reactive protein (CRP) increased HUVEC lysis in a dose-dependent fashion.
  
  
  CONCLUSIONS
  In patients with UA, CD4 T cells undergo a change in functional profile and acquire cytotoxic capability. Cytotoxic CD4 T cells effectively kill endothelial cells; CRP sensitizes endothelial cells to the cytotoxic process. We propose that T-cell-mediated endothelial cell injury is a novel pathway of tissue damage that contributes to plaque destabilization. The sensitizing effect of CRP suggests synergy between dysregulated T-cell function and acute phase proteins in acute coronary syndromes.
authors.affiliation: Department of Medicine, Division of Cardiology, Mayo Clinic, Rochester, Minnesota, USA.
authors.forename: Takako
authors.initials: T
authors.lastname: Nakajima
authors.forename: Stephanie
authors.initials: S
authors.lastname: Schulte
authors.forename: Kenneth J
authors.initials: KJ
authors.lastname: Warrington
authors.forename: Stephen L
authors.initials: SL
authors.lastname: Kopecky
authors.forename: Robert L
authors.initials: RL
authors.lastname: Frye
authors.forename: Jörg J
authors.initials: JJ
authors.lastname: Goronzy
authors.forename: Cornelia M
authors.initials: CM
authors.lastname: Weyand
mesh_terms: D000208:Acute Disease; D000368:Aged; D000789:Angina, Unstable / Q000150:complications / Q000276:immunology; D000954:Antigens, Surface / Q000096:biosynthesis; D015551:Autoimmunity; D002097:C-Reactive Protein / Q000494:pharmacology; D018106:CD28 Antigens / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D002478:Cells, Cultured; D002999:Clone Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D003324:Coronary Artery Disease / Q000150:complications / Q000276:immunology*; D003601:Cytotoxicity Tests, Immunologic; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000276:immunology*; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D037181:Lectins, C-Type; D008562:Membrane Glycoproteins / Q000096:biosynthesis; D008875:Middle Aged; D055651:NK Cell Lectin-Like Receptor Subfamily B; D054353:Perforin; D052899:Pore Forming Cytotoxic Proteins; D013324:Strontium / Q000494:pharmacology; D016176:T-Lymphocyte Subsets / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D013602:T-Lymphocytes, Cytotoxic / Q000166:cytology / Q000187:drug effects / Q000276:immunology / Q000378:metabolism
chemical_list: D000954:Antigens, Surface; D018106:CD28 Antigens; C527203:KLRB1 protein, human; D037181:Lectins, C-Type; D008562:Membrane Glycoproteins; D055651:NK Cell Lectin-Like Receptor Subfamily B; D052899:Pore Forming Cytotoxic Proteins; D054353:Perforin; D002097:C-Reactive Protein; D013324:Strontium