TY - JOUR
T1 - Regulatory T cells modulate postischemic neovascularization
AU - Zouggari, Yasmine
AU - Ait-Oufella, Hafid
AU - Waeckel, Ludovic
AU - Vilar, José
AU - Loinard, Céline
AU - Cochain, Clément
AU - Récalde, Alice
AU - Duriez, Micheline
AU - Levy, Bernard I.
AU - Lutgens, Ester
AU - Mallat, Ziad
AU - Silvestre, Jean Sébastien
PY - 2009/10
Y1 - 2009/10
N2 - 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 CD4CD25 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. METHODS AND 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. CONCLUSION-: Treg cell response modulates postischemic neovascularization.
AB - 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 CD4CD25 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. METHODS AND 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. CONCLUSION-: Treg cell response modulates postischemic neovascularization.
KW - Angiogenesis
KW - Cells
KW - Inflammation
KW - Ischemia
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U2 - 10.1161/CIRCULATIONAHA.109.875583
DO - 10.1161/CIRCULATIONAHA.109.875583
M3 - Article
C2 - 19770391
AN - SCOPUS:70349753270
SN - 0009-7322
VL - 120
SP - 1415
EP - 1425
JO - Circulation
JF - Circulation
IS - 14
ER -