title: Insufficient deactivation of the protein tyrosine kinase lck amplifies T-cell responsiveness in acute coronary syndrome.
abstract: BACKGROUND
  In the vulnerable atherosclerotic plaque, T cells may destabilize the tissue structure through direct cell-injurious effector functions. T cells transmit environmental signals, such as recognition of antigen, into cellular responses through regulated phosphorylation of cytoplasmic proteins, with the Src family kinase Lck (lymphocyte-specific protein tyrosine kinase) in critical membrane-proximal position of the T-cell receptor (TCR) signaling cascade. The balance between protein phosphorylation and dephosphorylation defines the signal transduction threshold and determines appropriate T-cell responses.
  
  
  OBJECTIVE
  We have examined whether abnormal calibration of intracellular signaling pathways renders acute coronary syndrome (ACS) patients susceptible to disproportionate T-cell responses.
  
  
  RESULTS
  Intracellular signaling cascades were quantified in CD4 T cells from ACS patients and control individuals after stimulation with major histocompatibility complex class II-superantigen complexes. ACS T cells mobilized more intracellular calcium and accumulated higher levels of phosphotyrosine than control T cells. Proximal steps in TCR signaling, such as recruitment of ZAP-70 and clustering of TCR complexes in the immune synapse, were abnormally enhanced in ACS T cells. Acceleration of the signaling cascade derived from a proximal defect in ACS T cells, which failed to phosphorylate Lck at Tyr505, extending activation of the Src kinase. Abnormalities in TCR signaling did not correlate with systemic inflammation as measured by C-reactive protein.
  
  
  CONCLUSIONS
  An intrinsic abnormality in the signaling machinery of ACS T cells resulting in the accumulation of active Lck lowers the TCR threshold and renders lymphocytes hyperreactive and capable of unwanted immune responses.
authors.affiliation: Lowance Center for Human Immunology and Rheumatology, Emory University, Atlanta, GA, USA.
authors.forename: Sergey
authors.initials: S
authors.lastname: Pryshchep
authors.forename: Jörg J
authors.initials: JJ
authors.lastname: Goronzy
authors.forename: Susmita
authors.initials: S
authors.lastname: Parashar
authors.forename: Cornelia M
authors.initials: CM
authors.lastname: Weyand
mesh_terms: D054058:Acute Coronary Syndrome / Q000201:enzymology* / Q000276:immunology; D000938:Antigen-Presenting Cells / Q000276:immunology; D015415:Biomarkers / Q000097:blood; D002097:C-Reactive Protein / Q000378:metabolism; D017252:CD3 Complex / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000201:enzymology* / Q000276:immunology; D020013:Calcium Signaling; D016022:Case-Control Studies; D002478:Cells, Cultured; D018920:Coculture Techniques; D004768:Enterotoxins / Q000276:immunology; D004789:Enzyme Activation; D005260:Female; D000949:Histocompatibility Antigens Class II / Q000276:immunology; D006801:Humans; D054992:Immunological Synapses / Q000201:enzymology; D018836:Inflammation Mediators / Q000097:blood; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D010766:Phosphorylation; D019000:Phosphotyrosine / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000276:immunology; D015398:Signal Transduction; D018089:Superantigens; D013997:Time Factors; D051746:ZAP-70 Protein-Tyrosine Kinase / Q000378:metabolism
chemical_list: D015415:Biomarkers; D017252:CD3 Complex; D004768:Enterotoxins; D000949:Histocompatibility Antigens Class II; D018836:Inflammation Mediators; D011948:Receptors, Antigen, T-Cell; D018089:Superantigens; D019000:Phosphotyrosine; C031818:enterotoxin B, staphylococcal; D002097:C-Reactive Protein; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck); D051746:ZAP-70 Protein-Tyrosine Kinase; C497261:ZAP70 protein, human