title: 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.
  
  
  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 Cd80(-/-)/Cd86(-/-) or 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 Cd28(-/-) Treg-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 Treg cells and IL-10 in the control of aneurysm formation and its progression to rupture and suggest that therapies targeting Treg responses may be most suited to treat aneurysmal disease.
authors.affiliation: From the Institut National de la Santé et de la Recherche Médicale (Inserm), Unit 970, Paris Cardiovascular Research Center, Université Paris-Descartes, Paris, France (H.A.-O., Y.W., O.H., S.B., S.P., J.J., X.L., P.P., B.E., M.D., L.L., A.T., Z.M.); Service de Réanimation Médicale, Hôpital Saint-Antoine, Université Pierre-et-Marie Curie, Paris, France (H.A.-O.); and Division of Cardiovascular Medicine, Department of Medicine, Addenbrooke's Hospital, University of Cambridge, Cambridge, United Kingdom (Z.M.).
authors.forename: Hafid
authors.initials: H
authors.lastname: Ait-Oufella
authors.forename: Yu
authors.initials: Y
authors.lastname: Wang
authors.forename: Olivier
authors.initials: O
authors.lastname: Herbin
authors.forename: Simon
authors.initials: S
authors.lastname: Bourcier
authors.forename: Stephane
authors.initials: S
authors.lastname: Potteaux
authors.forename: Jeremie
authors.initials: J
authors.lastname: Joffre
authors.forename: Xavier
authors.initials: X
authors.lastname: Loyer
authors.forename: Padmapria
authors.initials: P
authors.lastname: Ponnuswamy
authors.forename: Bruno
authors.initials: B
authors.lastname: Esposito
authors.forename: Marion
authors.initials: M
authors.lastname: Dalloz
authors.forename: Ludivine
authors.initials: L
authors.lastname: Laurans
authors.forename: Alain
authors.initials: A
authors.lastname: Tedgui
authors.forename: Ziad
authors.initials: Z
authors.lastname: Mallat
mesh_terms: D000804:Angiotensin II; D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D001012:Aorta, Abdominal / Q000276:immunology* / Q000473:pathology; D017544:Aortic Aneurysm, Abdominal / Q000139:chemically induced / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D001019:Aortic Rupture / Q000139:chemically induced / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D018122:B7-1 Antigen / Q000172:deficiency / Q000235:genetics; D051940:B7-2 Antigen / Q000172:deficiency / Q000235:genetics; D018106:CD28 Antigens / Q000172:deficiency / Q000235:genetics; D002478:Cells, Cultured; D018920:Coculture Techniques; D004195:Disease Models, Animal; D018836:Inflammation Mediators / Q000378:metabolism; D016753:Interleukin-10 / Q000172:deficiency / Q000235:genetics; D053645:Interleukin-2 Receptor alpha Subunit / Q000276:immunology; D047589:Leukocyte Reduction Procedures; D008213:Lymphocyte Activation; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000637:transplantation; D013997:Time Factors
chemical_list: D000911:Antibodies, Monoclonal; D018122:B7-1 Antigen; D051940:B7-2 Antigen; D018106:CD28 Antigens; C497965:Cd86 protein, mouse; C556062:IL10 protein, mouse; C508018:Il2ra protein, mouse; D018836:Inflammation Mediators; D053645:Interleukin-2 Receptor alpha Subunit; D000804:Angiotensin II; D016753:Interleukin-10
keywords: aneurysm; cytokines; immunity; lymphocytes