CD4 Foxp3 T-cells contribute to myocardial ischemia-reperfusion injury.

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 30minutes of coronary ligation followed by 24hours 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 24hours 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 24hours 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.