title: Regulatory T cells modulate postischemic neovascularization.
abstract: BACKGROUND
  CD4+ and CD8+ T lymphocytes are key regulators of postischemic neovascularization. T-cell activation is promoted by 2 major costimulatory signalings, the B7/CD28 and CD40-CD40 ligand pathways. Interestingly, CD28 interactions with the structurally related ligands B7-1 and B7-2 are also required for the generation and homeostasis of CD4+CD25+ regulatory T cells (Treg cells), which play a critical role in the suppression of immune responses and the control of T-cell homeostasis. We hypothesized that Treg cell activation may modulate the immunoinflammatory response to ischemic injury, leading to alteration of postischemic vessel growth.
  
  
  RESULTS
  Ischemia was induced by right femoral artery ligation in CD28-, B7-1/2-, or CD40-deficient mice (n=10 per group). CD40 deficiency led to a significant reduction in the postischemic inflammatory response and vessel growth. In contrast, at day 21 after ischemia, angiographic score, foot perfusion, and capillary density were increased by 2.0-, 1.2-, and 1.8-fold, respectively, in CD28-deficient mice, which showed a profound reduction in the number of Treg cells compared with controls. Similarly, disruption of B7-1/2 signaling or anti-CD25 treatment and subsequent Treg deletion significantly enhanced postischemic neovascularization. These effects were associated with enhanced accumulation of CD3-positive T cells and Mac-3-positive macrophages in the ischemic leg. Conversely, treatment of CD28(-/-) mice with the nonmitogenic anti-CD3 monoclonal antibody enhanced the number of endogenous Treg cells and led to a significant reduction of the postischemic inflammatory response and neovascularization. Finally, coadministration of Treg cells and CD28(-/-) splenocytes in Rag1(-/-) mice with hindlimb ischemia abrogated the CD28(-/-) splenocyte-induced activation of the inflammatory response and neovascularization.
  
  
  CONCLUSIONS
  Treg cell response modulates postischemic neovascularization.
authors.affiliation: Paris-Cardiovascular Research Center, INSERM U970, Hôpital Européen Georges Pompidou, Université Paris 5, 75015 Paris, France.
authors.forename: Yasmine
authors.initials: Y
authors.lastname: Zouggari
authors.forename: Hafid
authors.initials: H
authors.lastname: Ait-Oufella
authors.forename: Ludovic
authors.initials: L
authors.lastname: Waeckel
authors.forename: José
authors.initials: J
authors.lastname: Vilar
authors.forename: Céline
authors.initials: C
authors.lastname: Loinard
authors.forename: Clément
authors.initials: C
authors.lastname: Cochain
authors.forename: Alice
authors.initials: A
authors.lastname: Récalde
authors.forename: Micheline
authors.initials: M
authors.lastname: Duriez
authors.forename: Bernard I
authors.initials: BI
authors.lastname: Levy
authors.forename: Esther
authors.initials: E
authors.lastname: Lutgens
authors.forename: Ester
authors.initials: E
authors.lastname: Lutgens
authors.forename: Ziad
authors.initials: Z
authors.lastname: Mallat
authors.forename: Jean-Sébastien
authors.initials: JS
authors.lastname: Silvestre
mesh_terms: D000818:Animals; D018122:B7-1 Antigen / Q000235:genetics / Q000276:immunology; D051940:B7-2 Antigen / Q000235:genetics / Q000276:immunology; D018106:CD28 Antigens / Q000235:genetics / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D019013:CD40 Antigens / Q000172:deficiency / Q000235:genetics / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D002196:Capillaries / Q000276:immunology; D005434:Flow Cytometry; D006614:Hindlimb; D007150:Immunohistochemistry; D007511:Ischemia / Q000276:immunology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D017202:Myocardial Ischemia / Q000276:immunology*; D009389:Neovascularization, Pathologic / Q000276:immunology; D018919:Neovascularization, Physiologic; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D018122:B7-1 Antigen; D051940:B7-2 Antigen; D018106:CD28 Antigens; D019013:CD40 Antigens; D042461:Vascular Endothelial Growth Factor A