CD31 is a transmembrane molecule endowed with T cell regulatory functions owing to the presence of 2 immunotyrosine-based inhibitory motifs. For reasons not understood, CD31 is lost by a portion of circulating T lymphocytes, which appear prone to uncontrolled activation. In this study, we show that extracellular T cell CD31 comprising Ig-like domains 1 to 5 is cleaved and shed from the surface of human T cells upon activation via their TCR. The shed CD31 can be specifically detected as a soluble, truncated protein in human plasma. CD31 shedding results in the loss of its inhibitory function because the necessary cis-homo–oligomerization of the molecule, triggered by the trans-homophilic engagement of the distal Ig-like domain 1, cannot be established by CD31shed cells. However, we show that a juxta-membrane extracellular sequence, comprising part of the domain 6, remains expressed at the surface of CD31shed T cells. We also show that the immunosuppressive CD31 peptide aa 551–574 is highly homophilic and possibly acts by homo-oligomerizing with the truncated CD31 remaining after its cleavage and shedding. This peptide is able to sustain phosphorylation of the CD31 ITIM686 and of SHP2 and to inhibit TCR-induced T cell activation. Finally, systemic administration of the peptide in BALB/c mice efficiently suppresses Ag-induced T cell-mediated immune responses in vivo. We conclude that the loss of T cell regulation caused by CD31 shedding driven by TCR stimulation can be rescued by molecular tools able to engage the truncated juxta-membrane extracellular molecule that remains exposed at the surface of CD31shed cells.

Background— Cell-mediated immunity is considered to contribute to the pathogenesis of abdominal aortic aneurysms (AAA). In particular, infiltrating macrophages and CD8 + T lymphocytes participate in the destruction of the aortic wall extracellular matrix and smooth muscle cells. We surmise that these pathological events are controlled by circulating regulatory lymphocytes. Methods and Results— Circulating CD4 + /CD31 + cells were reduced in AAA patients (n=80, 8.9±0.6%) as compared with controls (n=69, 13.7±0.8%; P <0.001) and inversely proportional to AAA size. Exclusion of the aneurysm by an endoprothesis did not affect CD31 + T cell values. Reduction of blood CD4 + /CD31 + cells was not attributable to their enrichment in AAA tissue. In contrast, CD8 + /CD31 + cells were slightly reduced in the blood while increased in the aneurysmal tissue (29.2±0.5 versus 20.2±4.7% in blood, n=6; P <0.05). Remarkably, high percentages of CD4 + /CD31 + cells were able to regulate proliferation and cytokine production of CD8 + lymphocytes, as well as CD8 + cell-mediated cytotoxicity of aortic smooth muscle cells ( P <0.01). Finally, CD4 + /CD31 + cells reduced the production and activity of metalloproteinase-9 by lipopolysaccharide-stimulated macrophages. Conclusions— Circulating CD4 + /CD31 + T cells regulate macrophage and CD8 + T cell activation and effector function in the arterial wall. Their reduction might promote the development of AAA.

Objective-The contribution of thrombosis and coagulation in atherogenesis is largely unknown. We investigated the contribution of the coagulation intrinsic factor VIII (FVIII)-dependent pathway in atherogenesis. Methods and Results-Apolipoprotein E and FVIII double-deficient mice (E°/FVIII°) were generated. Aortic root lesions were analyzed in 14-week-old and 22-week-old female mice maintained for 8 or 16 weeks, respectively, on a normal chow diet or a hypercholesterolemic diet. Conclusion-Despite a higher plasma total cholesterol concentration compared with E°mice, E°/FVIII°mice developed dramatically less early-stage atherosclerotic lesions. Whereas early lesions in E°mice contained abundant fibrin(ogen) deposits on which few platelets adhered, lesions in E°/FVIII°were almost devoid of fibrin(ogen), and no platelets could be detected. Key Words: atherosclerosis Ⅲ hemophilia Ⅲ mouse Ⅲ knockout C omplications of atherosclerosis are the main causes of death in industrialized countries. The current paradigm establishes procoagulant state and thrombosis to be the major reason for complications. Consequently, it has been assumed that thrombosis and coagulation would also be involved in lesion formation. For instance, it is known that platelet activation and adhesion occur during the very first steps of the disease, 1 and the presence of the coagulation factor VIII (FVIII) has been reported in the vicinity of macrophages and smooth muscle cells in human atherectomy specimens. 2 Yet, the contribution of coagulation and thrombosis in atherogenesis remains largely unknown. Apolipoprotein E knockout (E°) mice are a reference model for experimental atherosclerosis. 3,4 As a result of their severe hypercholesterolemia, which can be aggravated by a hypercholesterolemic diet, these mice develop all stages of disease, from early fatty lesions through to mature fibrofatty plaques. 5 The present study was aimed at determining the influence of the intrinsic coagulation pathway in atherogenesis by analyzing lesion development in E°mice deficient for the FVIII. We found that the absence of this coagulation factor has a strong impact on the early stage of lesion formation. Materials and Methods Generation of E°/FVIII°MiceE°/FVIII°double-deficient mice were generated by crossing E°and FVIII°single knockout mice. FVIII°mice were provided kindly by Dr Kazazian 6,7 (University of Pennsylvania, Philadelphia). E°, FVIII°, and E°/FVIII°F2 offspring were used to establish the 3 genotype colonies. The genotyping was performed by polymerase chain reaction on DNA extracted from mouse tails. Experimental ProtocolsFive-to 6-week-old E°/FVIII°, control E°, and FVIII°female mice were placed on a normal chow diet (ND) or a hypercholesterolemic 0.15% cholesterol Western diet (WD) for 8 or 16 weeks (respectively, the "8-week protocol" and the "16-week protocol"). Weights were measured at death. All experiments were approved by our institutional ethical committee. Plasma MeasurementsCitrated blood collected at death was centrifuged at 4°C for 5 minut...