observed similar atherosclerotic lesion development compared with control ApoE-deficient mice after 12 weeks on the WTD [42]

observed similar atherosclerotic lesion development compared with control ApoE-deficient mice after 12 weeks on the WTD [42]. 16 or 24 weeks, respectively. In all experimental groups investigated, we failed to detect any influence of TGF?1 overexpression on disease. Total number of CD3-positive T-lymphocytes was not significantly different in atherosclerotic lesions of CD2-TGF?1 ApoE?/? females and isogenic ApoE?/? controls, even after 24 weeks on the atherogenic diet. The synopsis of these data and our previous study on TGF?1 overexpressing macrophages suggests that potential effects of TGF?1 on atherosclerosis are most probably mediated by macrophages rather than T-cells. Introduction The pleiotropic cytokine TGF?1 can exert multiple immunomodulatory effects [1], [2] which is impressively reflected by the respective phenotype of knock-out mice, dying pre- or perinatally because of widespread inflammatory reactions [3], [4]. TGF?1 is synthesized by several cardiovascular cell types involved into atherogenesis including endothelial cells, monocytes/macrophages and T-cells [5]. The potential of TGF?1 to inhibit the proliferation of smooth muscle cells (SMCs) and to induce the formation of extracellular matrix [6], [7] has led to the assumption that this cytokine may have anti-atherogenic properties [8]. This hypothesis is supported by clinical studies indicating a negative correlation between plasma TGF?1 concentrations and the extent of atherosclerosis [8], [9], [10]. Experimental inhibition of TGF?1 in blood vessels of atherosclerosis-prone ApoE knock-out mice by specific antibodies [11] or recombinant soluble type II receptor [12] resulted in accelerated atherosclerosis or a more pro-inflammatory plaque phenotype and thus principally confirmed the putative anti-atherogenic TGF?1 properties. Further, transgenic TGF?1 overexpression in the heart and plasma of atherosclerotic mice led to reduction of atherosclerosis and thus also supported the atheroprotective function of TGF?1 [13]. In an attempt to more specifically address the mechanisms underlying the effects of TGF?1 on atherogenesis, we have recently shown that overexpression of TGF?1 in macrophages reduces and stabilizes atherosclerotic plaques in ApoE?/? mice [14]. Concerning T cells, numerous studies have provided evidence for their involvement in atherosclerosis, Corticotropin Releasing Factor, bovine although the number of this cell type in the lesion is sparse [15]. Goyova et al. [16] and Robertson and co-workers [17] used crossing experiments or bone marrow transplantation to introduce transgenic T-cells into atherosclerosis-prone mice in which the TGF-?1 signal transduction was specifically inhibited by overexpression of a dominant negative form of the type II receptor. Although these two studies found opposite effects on lesion size, they were in general agreement that blockade POLDS of TGF-? signalling in T cells increased vascular inflammation (which itself is certainly atherogenic). However, the experimental approach of T-cell specific inhibition Corticotropin Releasing Factor, bovine of TGF-?1 signalling by overexpression of a dominant negative type II receptor must generally be considered as limited since the immunological phenotype of such mouse strains differs depending on expression pattern and promoters used [16], [17] and is significantly more moderate compared to mice where the TGFBR2 gene was T-cell specifically targeted using the conditional Cre/LoxP technology [18]. Stimulated by the experimental results of T-cell specific inhibition of TGF?1 signalling during atherogenesis [16], [19], the aim of the present study was to reciprocally investigate the influence of T-cell specific TGF?1 overexpression on atherosclerotic disease. To this end we used the CD2-TGF?1 transgenic mouse strain which represents a well characterized murine model of TGF?1 overexpression and activated regulatory T-cells [20], [21] previously shown to suppress disease development in murine models of colon cancer [22] and airway hyper-reactivity [23]. In comparison to non-transgenic controls, isolated CD3-positive splenocytes of CD2-TGF?1 transgenic mice express active TGF?1 and synthesize higher levels Corticotropin Releasing Factor, bovine of TGF?1 upon stimulation with an anti-CD3/CD28 mAb..