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Several studies have shown a significant contribution of T-cell-mediated immunity in the pathology of atherosclerosis. The CD40-CD154 pathway plays a critical role in T-cell-co-stimulation during the inflammatory events and promotes atherosclerosis development and destabilization. Another T-cell-activation pathway of extreme importance relies on the B7 (CD80/CD86)/CD28 molecules, which are expressed in atherosclerotic plaques. In order to better characterize the role of the B7/CD28 pathway in atherosclerosis, we generated chimeric mice. Low density lipoprotein-receptor (LDLr)-deficient mice were lethally irradiated and reconstituted with B7 (both CD80 and CD86)-/- (n=9), CD28-/- (n=11), or control C57Bl/6 (n=10) bone marrow. After 20 weeks of high fat diet, we found a remarkable and unexpected increase of the plaque size in the aortic sinus of both B7-/- (+132%; P< 0.0001) and CD28-/- mice (+107%; P< 0.0001) in comparison with controls (831065±34941µm2 in B7-/- mice, 742073±56445 µm2 in CD28-/- mice, 357848±17013µm2 in controls), despite similar cholesterol levels (12.65±0.51g/l in B7-/-; 11.20±0.80 g/l in CD28-/- and 12.41±0.44 g/l in controls). B7 or CD28 deficiency in bone marrow cells led to profound modifications of plaque composition, typical of very advanced atherosclerosis as revealed by the marked increase in collagen content (18.9±1.6% in B7-/- mice, 34.3±2.7% in CD28-/- mice and 6.3±1.1% in controls; P< 0.05) and the decrease in macrophage accumulation (24±2.1% in B7-/- mice, 15.9±1.5 in CD28-/- and 34.5±1.4 in controls; P< 0.05). Interestingly, B7-/- and CD28-/- mice showed a profound decrease in the number of regulatory T cells (typically 0.98% of CD25 very high cells in the spleens of the deficient mice used here compared to 3.6% in wild type mice, i.e., 73% reduction), which may explain the unexpected detrimental role of B7/CD28 pathway in the development of advanced atherosclerosis.
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J. Vasc. Biol. 42, Sup:2 (2005) p81