Insufficient deactivation of the protein tyrosine kinase lck amplifies t-cell responsiveness in acute coronary syndrome

Sergey Pryshchep, Jörg J. Goronzy, Susmita Parashar, Cornelia M. Weyand

Research output: Contribution to journalArticlepeer-review

13 Scopus citations

Abstract

Rationale: 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. Methods and 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.

Original languageEnglish (US)
Pages (from-to)769-778
Number of pages10
JournalCirculation research
Volume106
Issue number4
DOIs
StatePublished - Mar 2010

Keywords

  • Calcium signaling
  • Protein tyrosine kinase
  • Signaling pathways
  • T cell

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

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