Foxp3+CD4+T Cells Improve Healing After Myocardial Infarction by Modulating Monocyte/Macrophage Differentiation

Rationale : An exaggerated or persistent inflammatory activation after myocardial infarction (MI) leads to maladaptive healing and subsequent remodeling of the left ventricle. Foxp3 + CD4 + regulatory T cells (T reg cells) contribute to inflammation resolution. Therefore, T reg cells might influence cardiac healing post-MI. Objective : Our aim was to study the functional role of T reg cells in wound healing post-MI in a mouse model of permanent left coronary artery ligation. Methods and Results : Using a model of genetic T reg -cell ablation (Foxp3 DTR mice), we depleted the T reg -cell compartment before MI induction, resulting in aggravated cardiac inflammation and deteriorated clinical outcome. Mechanistically, T reg -cell depletion was associated with M1-like macrophage polarization, characterized by decreased expression of inflammation-resolving and healing-promoting factors. The phenotype of exacerbated cardiac inflammation and outcome in T reg -cell–ablated mice could be confirmed in a mouse model of anti-CD25 monoclonal antibody–mediated depletion. In contrast, therapeutic T reg -cell activation by superagonistic anti-CD28 monoclonal antibody administration 2 days after MI led to improved healing and survival. Compared with control animals, CD28-SA–treated mice showed increased collagen de novo expression within the scar, correlating with decreased rates of left ventricular ruptures. Therapeutic T reg -cell activation induced an M2-like macrophage differentiation within the healing myocardium, associated with myofibroblast activation and increased expression of monocyte/macrophage-derived proteins fostering wound healing. Conclusions : Our data indicate that T reg cells beneficially influence wound healing after MI by modulating monocyte/macrophage differentiation. Moreover, therapeutic activation of T reg cells constitutes a novel approach to improve healing post-MI.