Background-Unstable atherosclerotic plaque is characterized by an infiltrate of inflammatory cells. Both macrophages and T cells have been implicated in mediating the tissue injury leading to plaque rupture; however, signals regulating their activation remain unidentified. Infectious episodes have been suspected to render plaques vulnerable to rupture. We therefore explored whether plasmacytoid dendritic cells (pDCs) that specialize in sensing bacterial and viral products can regulate effector functions of plaque-residing T cells and thus connect host infection and plaque instability. Methods and Results-pDCs were identified in 53% of carotid atheromas (nϭ30) in which they localized to the shoulder region and produced the potent immunoregulatory cytokine interferon (

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.

Activated and fully mature DC are represented in the inflammatory infiltrate characteristic for unstable carotid and coronary atheroma. Such DC produce chemokines, and thus can regulate the cell traffic into the lesion. Through the expression of the costimulatory ligand CD86, plaque-residing DC can augment T-cell stimulation and provide optimal stimulation conditions for T lymphocytes, resembling the microenvironment in organized lymphoid tissues.

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.

Objective An association between susceptibility to inflammatory bowel disease (IBD) and polymorphisms of both the tyrosine kinase 2 gene (TYK2) and the signal transducer and activator of transcription 3 gene (STAT3) was examined in a Japanese population in order to identify the genetic determinants of IBD. Methods The study subjects comprised 112 patients with ulcerative colitis, 83 patients with Crohn's disease (CD), and 200 healthy control subjects. Seven tag single-nucleotide polymorphisms (SNPs) in TYK2 and STAT3 were detected by PCR-restriction fragment length polymorphism. Results The frequencies of a C allele and its homozygous C/C genotype at rs2293152 SNP in STAT3 in CD patients were significantly higher than those in control subjects (P=0.007 and P=0.001, respectively). Furthermore, out of four haplotypes composed of the two tag SNPs (rs280519 and rs2304256) in TYK2, the frequencies of a Hap 1 haplotype and its homozygous Hap 1/Hap1 diplotype were significantly higher in CD patients in comparison to those in control subjects (P=0.023 and P=0.024, respectively). In addition, the presence of both the C/C genotype at rs2293152 SNP in STAT3 and the Hap 1/Hap 1 diplotype of TYK2 independently contributes to the pathogenesis of CD and significantly increases the odds ratio to 7.486 for CD (P=0.0008). Conclusion TYK2 and STAT3 are genetic determinants of CD in the Japanese population. This combination polymorphism may be useful as a new genetic biomarker for the identification of high-risk individuals susceptible to CD.