Insufficient Deactivation of the Protein Tyrosine Kinase Lck Amplifies T-Cell Responsiveness in Acute Coronary Syndrome
Year: 2009
Type: article
Study design: Observational Study
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.
Source: Circulation Research
Institutions: Emory University, Stanford Medicine, Stanford University
Language: English
Subfield: Immunology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: green
Awards: CD8 T Cells in Rheumatoid Arthritis, G1911962955, G2260927788, G2540523102, Oligoclonal T Cell Expansion and Rheumatoid Arthritis, G429955531, G464051429, G64106078, Ocular Disease in Giant Cell Arteritis, Interactions Between Inflammation, Oxidant Stress and Cardiovascular Disease, Vaccine and Infection Induced Immunity in the Young and Aged, G953332266, G971417677
OpenAlex ID: W2010762352