T Cell Recognition and Killing of Vascular Smooth Muscle Cells in Acute Coronary Syndrome

Abstract

Abstract-Loss of vascular smooth muscle cells (VSMCs) has been proposed to destabilize the atherosclerotic plaque and contribute to plaque rupture, superimposed thrombosis, and acute coronary syndromes (ACSs). We examined whether VSMCs are susceptible to T cell-induced apoptosis and found that CD4 T cells are highly effective in establishing cell-cell contact with VSMCs and triggering apoptotic death. Visualization of the T cell-VSMC contact zone on the single-cell level revealed that both patient-derived and control CD4 T cells reorganized their cell membrane to assemble an immunologic synapse with the VSMCs. Within 4 to 10 minutes, the membrane proximal signaling molecule ZAP-70 was recruited and phosphorylated. However, only patient-derived CD4 T cells sustained an intact immunologic synapse beyond 10 minutes and generated intracellular calcium signals. CD4 T cells that maintained a synaptic contact and appeared to be responsible for VSMC apoptosis accounted for approximately 20% of the circulating memory T cell population in ACS patients and were rare in the blood of age-matched controls. CD4 T cells from ACS patients were also hyperresponsive to T cell receptor-mediated stimulation when triggered by a superantigen and non-VSMC target cells. Lowered setting of the T cell activation threshold, attributable to excessive amplification of proximal CD3-mediated signals, may contribute to CD4 T cell-mediated killing of VSMCs and promote plaque instability.

A critical role for DAP10 and DAP12 in CD8+ T cell–mediated tissue damage in large granular lymphocyte leukemia

“…5,8,11,12 Moreover, activated CD8 ϩ CD28 null and CD4 ϩ CD28 null T lymphocytes are commonly overexpressed in autoimmune diseases. 9,[13][14][15][16] By microarray analysis, CD4 ϩ CD28 null T cells overexpressed perforin and several natural killer receptors (NKRs). Acquisition of non-MHC-restricted direct cytotoxicity against known NK tumor targets, normal tissue epithelial cells, and normal endothelial cells after activation in vitro suggested that these NKRs were functional.…”

“…9,[13][14][15] This activation can be initiated by activating NKRs that are expressed on both NK and T cells. Tissue epithelial or endothelial cells respond to stress by the display of cell surface ligands for activating NKRs leading to the recognition of activated For personal use only.…”

Fractalkine mediates T cell–dependent proliferation of synovial fibroblasts in rheumatoid arthritis

“…In that sense, intimal hyperplasia driven by vascular smooth muscle cells and synovial hyperplasia driven by FLS may share pathways of dysregulation. Vascular smooth muscle cells are now emerging as important partners of T cells in inflamed atherosclerotic plaques, not only because they are the subjects of T cell effector functions but also because they create synaptic communication platforms with tissue-infiltrating T cells (37,38).…”

Human Metapneumovirus SH and G Glycoproteins Inhibit Macropinocytosis-Mediated Entry into Human Dendritic Cells and Reduce CD4 + T Cell Activation

“…For each potential synapse detected (central clustering associated with a compensatory decrease in CD3 fluorescence in closely adjacent CD3-depleted membrane areas), the microscope was adjusted to give an additional ϫ7 magnification and a Z series of optical sections were performed at 0.3 m. Three-dimensional reconstruction of each potential synapse was performed using Imaris 7.3.0 (Bitplane, South Windsor, CT) to quantify the mean CD3 fluorescence intensity at the contact zone and on the remaining surface of the cell. An IS was defined as the clustering of labeled CD3 at the contact zone at a mean fluorescence intensity greater than 2-fold above the CD3 mean fluorescence intensity on the remaining surface of the cell (32,33). The contact zones that fulfilled these criteria were considered to represent ISs.…”