Purpose Unstable atherosclerotic plaque is characterized by an inflammatory infiltrate of macrophages and CD4 T cells. Traditionally, macrophages have been implicated in tissue injury. Less is known about the role of T cells. We have examined whether CD4 T cells interact with vascular smooth muscle cells (VSMC), how T cell-VSMC communication is regulated on the molecular level, and what the biological outcome is.
Methods CD4 T cells were isolated from peripheral blood of patients with acute myocardial infarction (AMI) and age/sex-matched controls and stimulated by VSMC monolayers. Alternatively, T-cell function was examined with non-VSMC antigen-presenting cells loaded with superantigen. T cell-VSMC contact zones were examined by confocal microscopy. Receptor-induced reorganization of the cytoskeleton was measured by the accumulation of F-actin. Target cell apoptosis was used as a biological outcome measure.
Results CD4 T cells from AMI patients but not those from controls rapidly induced apoptosis of VSMC. Apoptosis induction involved formation of an organized and sustained immunologic synapse and transfer of cytotoxic granules. To examine the role of antigen presented by VSMC in activating patient T cells, we compared patient and control T-cell responses to superantigen-loaded artificial target cells. Real-time confocal microscopy showed rapid movement of CD3 and LFA-1 to the contact zone for patient and control T cells. However, patient T cells recruited notably higher amounts of CD3-T cell receptor (TCR) complexes to the central region of the synapse within the first 4 min of conjugate formation (p = .006). By 10 min patient T cells had accumulated more F-actin molecules in the peripheral synapse (p < .05). Differences in membrane-proximal signals translated into stable synapse architecture in 63% of patient compared to 45% of control T cells (p = .03). Patient T cells forming a stable synapse efficiently induced target cell apoptosis (p < .05).
Conclusions CD4 T cells from AMI patients induce apoptosis of VSMC, a mechanism possibly associated with weakening of the fibrous cap, plaque destabilization, and plaque rupture. Apoptosis induction results from abnormal responsiveness of CD4 T cells that react to TCR ligation with enhanced recruitment of receptor complexes, faster reorganization of the cytoskeleton, and sustained stabilization of the synapse. Tuning down the activation threshold in such "trigger-happy " T cells may have therapeutic value for plaque stabilization.
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