Regulatory T cells modulate postischemic neovascularization

Yasmine Zouggari, Hafid Ait-Oufella, Ludovic Waeckel, José Vilar, Céline Loinard, Clément Cochain, Alice Récalde, Micheline Duriez, Bernard I. Levy, Ester Lutgens, Ziad Mallat, Jean Sébastien Silvestre

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish (US)
Pages (from-to)1415-1425
Number of pages11
Issue number14
StatePublished - Oct 2009


  • Angiogenesis
  • Cells
  • Inflammation
  • Ischemia

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)


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