TRAIL-expressing T cells induce apoptosis of vascular smooth muscle cells in the atherosclerotic plaque

Abstract

Acute coronary syndromes (ACS) are precipitated by a rupture of the atherosclerotic plaque, often at the site of T cell and macrophage infiltration. Here, we show that plaque-infiltrating CD4 T cells effectively kill vascular smooth muscle cells (VSMC). VSMCs sensitive to T cell–mediated killing express the death receptor DR5 (TNF-related apoptosis-inducing ligand [TRAIL] receptor 2), and anti-TRAIL and anti-DR5 antibodies block T cell–mediated apoptosis. CD4 T cells that express TRAIL upon stimulation are expanded in patients with ACS and more effectively induce VSMC apoptosis. Adoptive transfer of plaque-derived CD4 T cells into immunodeficient mice that are engrafted with human atherosclerotic plaque results in apoptosis of VSMCs, which was prevented by coadministration of anti-TRAIL antibody. These data identify that the death pathway is triggered by TRAIL-producing CD4 T cells as a direct mechanism of VSMC apoptosis, a process which may lead to plaque destabilization.

Apoptosis in the skeletal muscle of untreated children with juvenile dermatomyositis: Impact of duration of untreated disease

“…Our results suggested that DR4 was more involved than DR5 in apoptosis signaling for there was a positive correlation between DR4 and caspase 3 in the perivascular region. TRAIL has been shown to induce apoptosis of vascular smooth muscle cells from the atherosclerotic plague while anti-TRAIL and anti-DR5 antibodies blocked TRAIL-mediated apoptosis [22]. In contrast, osteoprotegerin (OPG), another receptor for TRAIL, inhibits TRAIL-induced apoptosis, due to the absence of a death domain [23].…”

Synergistic Proinflammatory Effects of the Antiviral Cytokine Interferon-α and Toll-Like Receptor 4 Ligands in the Atherosclerotic Plaque

“…This is particularly important for stressed plaque-residing vascular smooth muscle cells, which become the targets of cytotoxic T cells. 6,10 Current data widen the scope of potential biological functions of intraplaque IFN-␣, now encompassing regulation of mDC and macrophage sensitivity to TLR4 ligands. IFN-␣-facilitated recognition of TLR4 ligands may affect inflammatory activation not only in response to lipopolysaccharide and other microbial molecules 33 but also to (modified) endogenous molecules including heat-shock proteins, modified lipids, fibronectin, biglycan, and hyaluronan oligosaccharides, all abundantly present in the atherosclerotic lesion microenvironment.…”

“…In addition, IFN-␣ boosts the cytotoxic capacity of CD4 T cells, the main lymphocyte type in the atherosclerotic plaque. IFN-␣ enables CD4 T cells to kill stressed vascular smooth muscle cells in a TNF-related apoptosis-inducing ligand (TRAIL)-dependent way, 6,10 threatening the stability of atherosclerotic lesions. 11 The present study was designed to explore whether IFN-␣ produced in the plaque has immunoregulatory functions involving cell populations other than CD4 lymphocytes.…”

“…10 Acetone-fixed 5-m sections were incubated with anti-CD11c (1:200, Dako, Glostrup, Denmark), anti-fascin (Dako), anti-DC-sign (BD Pharmingen, San Jose, Calif), anti-CD123 (1:100, BD Pharmingen), and anti-IFN-␣ (1:400, BD Pharmingen) for 1 hour at room temperature. Five percent of goat serum was added to inhibit nonspecific staining.…”

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).…”