title: CD4+Foxp3+T-cells contribute to myocardial ischemia-reperfusion injury.
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.
  
  
  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.
authors: University Hospital Jena, Pharmacy, Erlanger Allee 101, 07747 Jena, Germany. Electronic address: denise.mathes@med.uni-jena.de.
authors: Denise
authors: D
authors: Mathes
authors: University Hospital Würzburg, Department of Internal Medicine I, Würzburg, Germany; University Hospital Würzburg, Comprehensive Heart Failure Center, Würzburg, Germany.
authors: Johannes
authors: J
authors: Weirather
authors: University Hospital Würzburg, Department of Internal Medicine I, Würzburg, Germany; University Hospital Würzburg, Comprehensive Heart Failure Center, Würzburg, Germany.
authors: Peter
authors: P
authors: Nordbeck
authors: University Hospital Würzburg, Department of Internal Medicine I, Würzburg, Germany.
authors: Anahi-Paula
authors: AP
authors: Arias-Loza
authors: University Hospital Würzburg, Department of Internal Medicine I, Würzburg, Germany; University Hospital Würzburg, Comprehensive Heart Failure Center, Würzburg, Germany.
authors: Matthias
authors: M
authors: Burkard
authors: University Hospital Würzburg, Department of Internal Medicine I, Würzburg, Germany; University Hospital Würzburg, Comprehensive Heart Failure Center, Würzburg, Germany.
authors: Christina
authors: C
authors: Pachel
authors: University of Würzburg, Institute for Virology and Immunobiology, Würzburg, Germany.
authors: Thomas
authors: T
authors: Kerkau
authors: University of Würzburg, Institute for Virology and Immunobiology, Würzburg, Germany.
authors: Niklas
authors: N
authors: Beyersdorf
authors: 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.
authors: Stefan
authors: S
authors: Frantz
authors: 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.
authors: Ulrich
authors: U
authors: Hofmann
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D015415:Biomarkers; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism*; D004195:Disease Models, Animal; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D051858:Forkhead Transcription Factors / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009203:Myocardial Infarction / Q000175:diagnosis / Q000209:etiology / Q000378:metabolism; D015428:Myocardial Reperfusion Injury / Q000175:diagnosis / Q000209:etiology* / Q000378:metabolism* / Q000628:therapy; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism*
chemical_list: D015415:Biomarkers; D018984:Epitopes, T-Lymphocyte; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse
keywords: CD4(+) T-cells; Myocardial ischemia-reperfusion injury; T-regulatory cells