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Objective The present study analyzed the effect of CD4 + Forkhead box protein 3 negative (Foxp3 − ) T-cells and Foxp3 + CD4 + T-cells on infarct size in a mouse myocardial ischemia-reperfusion model. Approach and results We examined the infarct size as a fraction of the area-at-risk as primary study endpoint in mice after 30 minutes of coronary ligation followed by 24 hours of reperfusion. CD4 + T-cell deficient MHC-II KO mice showed smaller histologically determined infarct size (34.5 ± 4.7% in MHCII KO versus 59.4 ± 4.9% in wildtype (WT)) and better preserved ejection fraction determined by magnetic resonance tomography (56.9 ± 2.8% in MHC II KO versus 39.0 ± 4.2% in WT). MHC-II KO mice also displayed better microvascular perfusion than WT mice after 24 hours of reperfusion. Also CD4 + T-cell sufficient OT-II mice, which express an in this context irrelevant T-cell receptor, revealed smaller infarct sizes compared to WT mice. However, MHC-II blocking anti-I-A/I-E antibody treatment was not able to reduce infarct size indicating that autoantigen recognition is not required for the activation of CD4 + T-cells during reperfusion. Flow-cytometric analysis also did not detect CD4 + T-cell activation in heart draining lymph nodes in response to 24 hours of ischemia-reperfusion. Adoptive transfer of CD4 + T-cells in CD4 KO mice increased the infarct size only when including the Foxp3 + CD25 + subset. Depletion of CD4 + Foxp3 + T-cells in DEREG mice enabling specific conditional ablation of this subset by treatment with diphtheria toxin attenuated infarct size as compared to diphtheria toxin treated WT mice. Conclusions CD4 + Foxp3 + T-cells enhance myocardial ischemia-reperfusion injury. CD4 + T-cells exert injurious effects without the need for prior activation by MHC-II restricted autoantigen recognition.

Background— Activation of innate immunity, especially infiltration of monocytes, is critical for proper wound healing and scar formation after myocardial infarction (MI). Therefore, we tested the hypothesis that interleukin-13 (IL-13), which influences the differentiation of monocytes/macrophages and has profibrotic properties, modulates wound healing and remodeling after MI. Methods and Results— MI was induced by permanent ligation of the left coronary artery in both male and female wild-type (WT)/IL-13 −/− mice. Real-time polymerase chain reaction demonstrated that expression of IL-13 was induced in left and right ventricular myocardium of WT mice within days in response to MI. Fifty-six–day survival was significantly impaired (65% in WT versus 34% in IL-13 −/− ) in male but not female IL-13 −/− (55% in WT versus 54% in IL-13 −/− ) mice. Serial echocardiography showed significantly increased left ventricular dilation in male IL-13 −/− compared with WT mice starting from day 1 after MI, despite comparable infarct size. Fluorescence-activated cell sorter analysis revealed less leukocyte infiltration in male IL-13 −/− mice on day 3. Real-time polymerase chain reaction analysis demonstrated reduced expression of marker genes of alternative activation in monocytes sorted from the infarct zone of male IL-13 −/− in comparison with WT mice on day 3 after MI. Conclusions— Genetic deficiency of IL-13 worsens outcome after MI in male mice. Our data indicate that IL-13 regulates leukocyte recruitment and induces M2-like monocyte/macrophage differentiation, which modifies wound healing within the infarct zone.