Opposite role of CD4+CD25+ regulatory T cells and T helper 1 lymphocytes in collateral vessels development

Background: Development of collateral blood vessels is an important compensatory mechanism in response to impaired blood flow due to artery occlusion/stenosis. Several inflammatory cell subpopulations including T lymphocytes are involved in such process. Stabile and colleagues showed that CD4+ and CD8+ T cell subsets are both necessary for efficient arteriogenesis. However the contribution of different CD4+ T cell subsets such as T helper (Th) or the immunosuppressive regulatory CD4+CD25+ T cells (Treg) in collateral responses is largely unknown. Aim of the study: The present study aims at characterizing the role of Th1, Th2 and Treg in the growth of collateral vasculature following artery occlusion. Methods: A mouse model of peripheral ischemia by surgical femoral artery occlusion (hindlimb ischemia model) in CD4 knockout mice (CD4-/-) lacking CD4 T cells was used. These mice displaying impaired collateral responses, were used as recipients in rescue experiments in which was studied the effect of i.v. injection (reconstitution) of different CD4+ T cell subsets purified from wild-type animals. Blood perfusion and limb function impairment were measured over time by laser Doppler imaging and by a semiquantitaive ambulatory impairment clinical score, respectively. Results: Reconstitution with CD4+ naïve (composed of effector cells) but not memory T cells (comprising both effector and Treg) restored the capacity to recover blood flow and limb function of CD4-/- mice. In addition CD4+ memory T cells depleted of the Treg cell subset were effective in restoring collateral response in recipient animals. Furthermore in vitro polarized Th1 but not Th2 cells supported the recovery of blood perfusion and limb function following femoral artery occlusion. Conclusions: Altogether these data indicate that Th1 but not Th2 cells act as positive regulators of collateral vessels development while Treg cells inhibit such response. The identification of specific circulating cellular subsets playing either as positive or negative regulators of collaterals growth may be exploited for the identification of novel easily detectable molecular markers for the assessment of the individual capacity to compensate vascular occlusion and for the design of novel therapeutic approaches for peripheral and cardiac ischemic diseases