title: Increased PTPN22 expression and defective CREB activation impair regulatory T-cell differentiation in non-ST-segment elevation acute coronary syndromes.
abstract: BACKGROUND
  Critical impairment of adaptive immune response has been observed in patients with acute coronary syndromes (ACS) with reduced expansion of regulatory T cells (Treg) and enhanced effector T-cell responsiveness, both associated with poorer outcomes.
  
  
  OBJECTIVE
  This study investigated the mechanisms underlying T-cell dysregulation in ACS.
  
  
  METHODS
  We evaluated both early and downstream T-cell receptor activation pathways after ex vivo stimulation with anti-CD3 and anti-CD28 crosslink in CD4(+) T cells from 20 patients with non-ST-segment elevation myocardial infarction (NSTEMI), 20 with stable angina (SA), and 20 controls. We reassessed 10 NSTEMI and 10 SA patients after 1 year.
  
  
  RESULTS
  Phospho-flow analysis revealed reduced phosphorylation of the zeta-chain-associated protein kinase of 70 kDa at the inhibitory residue tyrosine 292, enhancing T-cell activation, in NSTEMI helper T cells versus SA and controls (each, p < 0.001), resulting from increased expression of the protein tyrosine phosphatase, nonreceptor type, 22 (PTPN22) (p < 0.001 for both comparisons), persisting at follow-up. We also observed reduced phosphorylation (p < 0.001 versus controls) and lower levels of binding to interleukins 2 and 10 core promoter regions of the transcription factor cyclic adenosine monophosphate response element-binding protein (CREB) in NSTEMI (p < 0.05 vs. controls), which recovered at 1 year. Finally, in NSTEMI patients, helper T cells had a reduced ability in T-cell receptor-induced Treg generation (p = 0.002 vs. SA; p = 0.001 vs. controls), partially recovered at 1 year. Restoring CREB activity and silencing PTPN22 enhanced NSTEMI patients' ability to generate Treg.
  
  
  CONCLUSIONS
  The persistent overexpression of PTPN22 and the transient reduction of CREB activity, associated with impaired Treg differentiation, might play a role in ACS.
authors: Institute of Cardiology, Catholic University, Rome, Italy.
authors: Davide
authors: D
authors: Flego
authors: Institute of Cardiology, Catholic University, Rome, Italy.
authors: Anna
authors: A
authors: Severino
authors: Institute of Cardiology, Catholic University, Rome, Italy.
authors: Francesco
authors: F
authors: Trotta
authors: Institute of Cardiology, Catholic University, Rome, Italy.
authors: Marco
authors: M
authors: Previtero
authors: Institute of Cardiology, Catholic University, Rome, Italy.
authors: Sarassunta
authors: S
authors: Ucci
authors: Institute of Cardiology, Catholic University, Rome, Italy.
authors: Chiara
authors: C
authors: Zara
authors: Institute of Cardiology, Catholic University, Rome, Italy.
authors: Gianluca
authors: G
authors: Massaro
authors: Institute of Cardiology, Catholic University, Rome, Italy.
authors: Daniela
authors: D
authors: Pedicino
authors: Institute of Cardiology, Catholic University, Rome, Italy.
authors: Luigi M
authors: LM
authors: Biasucci
authors: Institute of Cardiology, Catholic University, Rome, Italy. Electronic address: giovanna.liuzzo@gmail.com.
authors: Giovanna
authors: G
authors: Liuzzo
authors: Institute of Cardiology, Catholic University, Rome, Italy.
authors: Filippo
authors: F
authors: Crea
mesh_terms: D054058:Acute Coronary Syndrome / Q000000981:diagnostic imaging / Q000235:genetics* / Q000276:immunology* / Q000401:mortality; D056704:Adaptive Immunity / Q000276:immunology*; D000368:Aged; D000704:Analysis of Variance; D000787:Angina Pectoris / Q000235:genetics / Q000276:immunology / Q000401:mortality; D050882:CREB-Binding Protein / Q000235:genetics*; D016022:Case-Control Studies; D017023:Coronary Angiography; D004562:Electrocardiography; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D008297:Male; D008875:Middle Aged; D009203:Myocardial Infarction / Q000235:genetics / Q000276:immunology / Q000401:mortality; D011379:Prognosis; D054596:Protein Tyrosine Phosphatase, Non-Receptor Type 22 / Q000235:genetics*; D012016:Reference Values; D018570:Risk Assessment; D015398:Signal Transduction; D015996:Survival Rate; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism
chemical_list: D050882:CREB-Binding Protein; C494363:CREBBP protein, human; C516765:PTPN22 protein, human; D054596:Protein Tyrosine Phosphatase, Non-Receptor Type 22
keywords: dysregulation; immune system; signaling pathway