title: Activated regulatory T-cells attenuate myocardial ischaemia/reperfusion injury through a CD39-dependent mechanism.
abstract: Regulatory T-cells (Tregs) are generally regarded as key immunomodulators that maintain immune tolerance and counteract tissue damage in a variety of immune-mediated disorders. However, its role in myocardial ischaemia/reperfusion injury (MIRI) remains unknown. The purpose of the present study was to determine whether Tregs exert a beneficial effect on mouse MIRI. We examined the role of Tregs in murine MIRI by depletion using 'depletion of regulatory T-cell' (DEREG) mice and adoptive transfer using Forkhead box P3 (Foxp3)-GFP knockin mice and the mechanisms of cardio protection were further studied in vivo and in vitro. Tregs rapidly accumulated in murine hearts following MIRI. Selective depletion of Tregs in the DEREG mouse model resulted in aggravated MIRI. In contrast, the adoptive transfer of in vitro-activated Tregs suppressed MIRI, whereas freshly isolated Tregs had no effect. Mechanistically, activated Treg-mediated protection against MIRI was not abrogated by interleukin (IL)-10 or transforming growth factor (TGF)-β1 inhibition but was impaired by the genetic deletion of cluster of differentiation 39 (CD39). Moreover, adoptive transfer of in vitro-activated Tregs attenuated cardiomyocyte apoptosis, activated a pro-survival pathway involving Akt and extracellular-signal-regulated kinase (ERK) and inhibited neutrophil infiltration, which was compromised by CD39 deficiency. Finally, the peripheral blood mononuclear cells of acute myocardial infarction (AMI) patients after primary percutaneous coronary intervention (PCI) revealed a decrease in CD4+CD25+CD127low Tregs and a relative increase in CD39+ cells within the Treg population. In conclusion, our data validated a protective role for Tregs in MIRI. Moreover, in vitro-activated Tregs ameliorated MIRI via a CD39-dependent mechanism, representing a putative therapeutic strategy.
authors.affiliation: *Laboratory of Cardiovascular Immunology, Institute of Cardiology, Union Hospital, Tongji Medical College of Huazhong University of Science and Technology; Laboratory of Biological Targeted Therapy of the Ministry of Education, Wuhan 430022, China.
authors.forename: Ni
authors.initials: N
authors.lastname: Xia
authors.affiliation: *Laboratory of Cardiovascular Immunology, Institute of Cardiology, Union Hospital, Tongji Medical College of Huazhong University of Science and Technology; Laboratory of Biological Targeted Therapy of the Ministry of Education, Wuhan 430022, China.
authors.forename: Jiao
authors.initials: J
authors.lastname: Jiao
authors.affiliation: *Laboratory of Cardiovascular Immunology, Institute of Cardiology, Union Hospital, Tongji Medical College of Huazhong University of Science and Technology; Laboratory of Biological Targeted Therapy of the Ministry of Education, Wuhan 430022, China.
authors.forename: Ting-Ting
authors.initials: TT
authors.lastname: Tang
authors.affiliation: *Laboratory of Cardiovascular Immunology, Institute of Cardiology, Union Hospital, Tongji Medical College of Huazhong University of Science and Technology; Laboratory of Biological Targeted Therapy of the Ministry of Education, Wuhan 430022, China.
authors.forename: Bing-Jie
authors.initials: BJ
authors.lastname: Lv
authors.affiliation: *Laboratory of Cardiovascular Immunology, Institute of Cardiology, Union Hospital, Tongji Medical College of Huazhong University of Science and Technology; Laboratory of Biological Targeted Therapy of the Ministry of Education, Wuhan 430022, China.
authors.forename: Yu-Zhi
authors.initials: YZ
authors.lastname: Lu
authors.affiliation: *Laboratory of Cardiovascular Immunology, Institute of Cardiology, Union Hospital, Tongji Medical College of Huazhong University of Science and Technology; Laboratory of Biological Targeted Therapy of the Ministry of Education, Wuhan 430022, China.
authors.forename: Ke-Jing
authors.initials: KJ
authors.lastname: Wang
authors.affiliation: *Laboratory of Cardiovascular Immunology, Institute of Cardiology, Union Hospital, Tongji Medical College of Huazhong University of Science and Technology; Laboratory of Biological Targeted Therapy of the Ministry of Education, Wuhan 430022, China.
authors.forename: Zheng-Feng
authors.initials: ZF
authors.lastname: Zhu
authors.affiliation: *Laboratory of Cardiovascular Immunology, Institute of Cardiology, Union Hospital, Tongji Medical College of Huazhong University of Science and Technology; Laboratory of Biological Targeted Therapy of the Ministry of Education, Wuhan 430022, China.
authors.forename: Xiao-Bo
authors.initials: XB
authors.lastname: Mao
authors.affiliation: *Laboratory of Cardiovascular Immunology, Institute of Cardiology, Union Hospital, Tongji Medical College of Huazhong University of Science and Technology; Laboratory of Biological Targeted Therapy of the Ministry of Education, Wuhan 430022, China.
authors.forename: Shao-Fang
authors.initials: SF
authors.lastname: Nie
authors.affiliation: †Center for Cardiovascular Genetics, Department of Molecular Cardiology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, U.S.A.
authors.forename: Qing
authors.initials: Q
authors.lastname: Wang
authors.affiliation: ‡Key Laboratory of Molecular Biophysics of the Ministry of Education, Cardio-X Institute, College of Life Science and Technology and Center of Human Genome Research, Huazhong University of Science and Technology, Wuhan 430074, China.
authors.forename: Xin
authors.initials: X
authors.lastname: Tu
authors.affiliation: §Department of Scientific Research, The 4th Hospital of Wuhan, Wuhan 430000, China.
authors.forename: Hong
authors.initials: H
authors.lastname: Xiao
authors.affiliation: *Laboratory of Cardiovascular Immunology, Institute of Cardiology, Union Hospital, Tongji Medical College of Huazhong University of Science and Technology; Laboratory of Biological Targeted Therapy of the Ministry of Education, Wuhan 430022, China.
authors.forename: Yu-Hua
authors.initials: YH
authors.lastname: Liao
authors.affiliation: ¶Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, U.S.A.
authors.forename: Guo-Ping
authors.initials: GP
authors.lastname: Shi
authors.affiliation: *Laboratory of Cardiovascular Immunology, Institute of Cardiology, Union Hospital, Tongji Medical College of Huazhong University of Science and Technology; Laboratory of Biological Targeted Therapy of the Ministry of Education, Wuhan 430022, China.
authors.forename: Xiang
authors.initials: X
authors.lastname: Cheng
mesh_terms: D019264:Adoptive Transfer / Q000379:methods; D000704:Analysis of Variance; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism*; D001081:Apyrase / Q000378:metabolism*; D051858:Forkhead Transcription Factors / Q000235:genetics; D055879:Gene Knock-In Techniques; D049452:Green Fluorescent Proteins / Q000235:genetics; D007167:Immunotherapy / Q000379:methods*; D008213:Lymphocyte Activation / Q000276:immunology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D015428:Myocardial Reperfusion Injury / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism
chemical_list: D015703:Antigens, CD; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D049452:Green Fluorescent Proteins; D001081:Apyrase; C067869:CD39 antigen