Regulatory T Cells Modulate Postischemic Neovascularization

Abstract

Background-CD4ϩ and CD8 ϩ 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 ϩ CD25 ϩ 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 (nϭ10 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 Ϫ/Ϫ 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 Ϫ/Ϫ splenocytes in Rag1 Ϫ/Ϫ mice with hindlimb ischemia abrogated the CD28 Ϫ/Ϫ splenocyte-induced activation of the inflammatory response and neovascularization.

Tissue-engineered vascular grafts transform into mature blood vessels via an inflammation-mediated process of vascular remodeling

“…Recent studies have suggested that regulatory T cells and NK cells may have a role in modulating postnatal neovascularization (41,42). Interestingly, in the hBMC-SCID/bg mouse model, a statistically significant difference in overall patency rates was not detected between BMC-seeded and unseeded scaffolds, which may be a reflection of the immunodeficient component of our mouse model.…”

VEGF induces signalling and angiogenesis by directing VEGFR2 internalisation through macropinocytosis

“…By contrast, macropinocytosis might allow VEGFR2 signalling by fulfilling one or more of the above functions. It is tempting to speculate that macropinocytosis might be responsible for delivering signalling complexes of the receptor to downstream targets, such as ERK1/2 and Akt, that could reside at specific endosomal compartments (Dobrowolski and De Robertis, 2012;McKay and Morrison, 2007;Miaczynska et al, 2004;Platta and Stenmark, 2011;Schenck et al, 2008;Sorkin and von Zastrow, 2009;Teis et al, 2002;Zouggari et al, 2009). Consequently, macropinocytosis would link VEGFR2 to the downstream cascades required to regulate complex angiogenic responses, such as survival (Karali et al, 2014), proliferation and migration of endothelial cells (Herbert and Stainier, 2011).…”

Regulation of collateral blood vessel development by the innate and adaptive immune system

“…The involvement of such T cell subsets in regulating collateral response to ischemia has been recently described. Using CD28-deficient mice that lack the Treg subset, or by depleting Tregs in wildtype animals by administering an anti-CD25 antibody, Zouggari and coworkers recently showed increased efficiency in blood flow recovery after femoral artery ligation [53]. The authors speculated that the suppressive effect of Tregs was due to their intrinsic inhibitory action on the effector immune cell response.…”