Denise Mathes1, Johannes Weirather2, Peter Nordbeck2, Anahi-Paula Arias-Loza3, Matthias Burkard2, Christina Pachel2, Thomas Kerkau4, Niklas Beyersdorf4, Stefan Frantz5, Ulrich Hofmann5. 1. University Hospital Jena, Pharmacy, Erlanger Allee 101, 07747 Jena, Germany. Electronic address: denise.mathes@med.uni-jena.de. 2. University Hospital Würzburg, Department of Internal Medicine I, Würzburg, Germany; University Hospital Würzburg, Comprehensive Heart Failure Center, Würzburg, Germany. 3. University Hospital Würzburg, Department of Internal Medicine I, Würzburg, Germany. 4. University of Würzburg, Institute for Virology and Immunobiology, Würzburg, Germany. 5. University Hospital Würzburg, Department of Internal Medicine I, Würzburg, Germany; University Hospital Würzburg, Comprehensive Heart Failure Center, Würzburg, Germany; Universitätsklinik und Poliklinik für Innere Medizin III, University Hospital Halle (Saale), Germany.
Abstract
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.
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.
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