Abstract 728: Natural CD4+CD25+ Regulatory T Cells Control The Development Of Abdominal Aortic Aneurysm
Abdominal aortic aneurysm (AAA) is characterized by a prominent inflammatory cell infiltrate and local destruction of extracellular matrix. Following the acute phase, the inflammatory infiltrate is predominately composed of T lymphocytes and macrophages. Mechanistic studies suggest that both Th1 and Th2-mediated responses may be involved in cell activation and matrix remodeling. CD4+CD25+Foxp3+ regulatory T cell (Treg) subset is specialized in the suppression of both Th1 and Th2 pathogenic immune responses and controls T cell homeostasis. We hypothesized that natural Treg cells control the immuno-inflammatory response and protect from aneurysm formation. Infusion of Angiotensin II (1 μg/kg/mn) for 28 days is an established methodology for AAA induction in Apoe−/− or ldlr−/− mice. However, normolipidemic, non atherosclerotic C57Bl/6 mice appear to be protected from this Ang II-induced arterial disease. We hypothesized that Treg deficiency in C57Bl/6 mice would alter this protection and promote AAA formation. CD28 deficiency leads to a profound reduction in Treg cells. To investigate the role of Treg deficiency in AAA formation, we infused Ang II into C57Bl/6 CD28+/+ (n=17) or CD28−/− mice (n=11). CD28 deficiency did not alter the pressor response to Ang II. Echocardiographic measurements performed 14 days after Ang II infusion revealed increased maximal aortic diameter in Ang II-infused CD28−/− mice (2.14±1.78 mm, n=6) versus Ang II-infused CD28+/+ mice (1.50 ± 0.06 mm, n=3; P< 0.02). Aortic diameter did not differ between CD28+/+ and CD28−/− mice infused with saline. At day 28, as expected, Ang II induced AAA in only 11.8% (2 out of 17) of CD28+/+ mice. CD28 deficiency markedly enhanced mice susceptibility to AAA, since 81.8% (9 out of 11) of CD28−/−mice showed AAA in response to Ang II (P<0.004 vs CD28+/+ mice). The frequency of thrombosed aneurysms was only 5.9% (1 out of 17) in CD28+/+ mice versus 63.6% (7 out of 11) in CD28−/− mice (P<0.002), of which 2 died after aneurysm rupture. In addition, aortic macrophage and T cell infiltration was markedly increased in the group of CD28−/− mice. These results highly suggest that natural Treg cells are efficient inhibitors of AAA formation in mice and may constitute an important therapeutic target.