Natural Regulatory T Cells Limit Angiotensin II–Induced Aneurysm Formation and Rupture in Mice

Abstract

Objective-Abdominal aortic aneurysm is an inflammatory disease leading to destructive vascular remodeling and ultimately to lethal aortic rupture. Despite its frequent association with atherosclerosis, compelling studies have shown striking differences and potentially opposite roles of T-cell helper responses in aneurysm as compared with atherosclerosis, casting doubt on the relevance and suitability of T-cell-targeted therapies in this context. Approach and Results-Here, we show that selective depletion of T regulatory (Treg) cells using a CD25-specific monoclonal antibody significantly enhances the susceptibility of C57Bl/6 mice to angiotensin II-induced abdominal aortic aneurysm and promotes aortic rupture (n=25-44 mice/group). Similar results are observed in angiotensin II-treated Cd80or Cd28 −/− mice with impaired Treg cell homeostasis (n=18-23 mice/group). Treg cell depletion is associated with increased immune cell activation and a blunted interleukin (IL)-10 anti-inflammatory response, suggesting an immunoinflammatory imbalance. Interestingly, Il-10 −/− mice (n=20 mice/group) show increased susceptibility to angiotensin II-induced abdominal aortic aneurysm and aortic rupture and are insensitive to Treg cell depletion. Finally, reconstitution of Cd28Treg-deficient mice with Treg cells (n=22 mice/group) restores a balance in the immunoinflammatory response, rescues the animals from increased susceptibility to aneurysm, and prevents aortic dissection. Conclusions-These results identify a critical role for Materials and MethodsMaterials and Methods are available in the online-only supplement. Figure 1A) led to important T-cell activation ( Figure 1B), significantly increased the incidence and severity of aneurysm, and predisposed to fatal aortic rupture ( Figure 1C and 1D). Enhanced susceptibility to AAA in Treg-depleted mice was associated with increased vascular accumulation of T cells ( Figure 1E) and marked elastin degradation ( Figure 1F). −/− mice (n=18) already at day 7 after angiotensin II (AngII) infusion compared with controls (n=18). This is associated with a significant increase of T-cell infiltration within the aortic wall of CD28 −/− mice infused with AngII (B), mostly in the adventitia (n=8/group). C, A shift of the immune response toward reduced ratio of Having established that genetic or antibody-induced Treg deficiency promotes AAA formation and rupture, we wanted to address the underlying mechanisms. We found that Treg-deficient Cd28 −/− mice displayed increased AAA development already at day 7 after AngII infusion ( Figure 3A), indicating an early acceleration of the disease in the absence of Treg cells. Enhanced susceptibility to AAA in Cd28 −/− mice was associated with increased vascular accumulation of leukocytes ( Figure I in the onlineonly Data Supplement), particularly T cells ( Figure 3B), and an imbalance of the systemic (spleen, Figure 3C) and local (aortic, Figure 3D) immunoinflammatory response as reflected by low interleukin (IL)-10 but high expression of IL-12 and inter...

Regulatory T Cells Prevent Angiotensin II–Induced Abdominal Aortic Aneurysm in Apolipoprotein E Knockout Mice

“…7 A recent study reported a beneficial effect of Tregs on an animal model of AAA although the dose-response effect and the underlying mechanisms remain unclear. 17 Our results provided complementary data and further documented that adoptive transfer of Tregs dose-dependently reduced the incidence and severity of angiotensin II-induced AAA in ApoE −/− mice. First, we found lower Foxp3 expression in human aortic aneurysmal tissues than in human normal thoracic aortic samples.…”

Regulatory T cells protect against hypoxia-induced pulmonary arterial hypertension in mice

“…The average purity of Tregs was >97%, as determined by fluorescence-activated cell sorting analysis (BD FACSCalibur; BD Biosciences, Franklin Lakes, NJ, USA). Cells were suspended in a total volume of 200 µl PBS for injection, as previously described (9,10,14). One day before exposure to hypoxic conditions, the mice in the control and Tregs groups were injected with PBS or Tregs (1x10 6 cells), respectively, into the tail vein.…”

“…Tregs have been reported to exert beneficial effects on the progression of numerous diseases (9,10), including atherlerosclerosis (11), abdominal aortic aneurysms (12) and inflammatory bowel disease (13). However, the role of Tregs in the development of PAH remains to be elucidated.…”

Foxp3 + Regulatory T Cells Play a Protective Role in Angiotensin II–Induced Aortic Aneurysm Formation in Mice

“…[9][10][11] We and others have shown the contribution of reduced Treg levels to the progression of human coronary artery disease. 12,13 Recently, CD4 + CD25 + Treg deficiency caused by genetic disruption of CD80/CD86 or CD28 costimulatory molecules has been shown to promote the development and rupture of angiotensin II-induced AAA in C57BL/6 wild-type mice, 14 suggesting a crucial role for endogenous CD4 + CD25…”