title: CD4(+)CD25 (+) regulatory T cells are not required for mesenchymal stem cell function in fully MHC-mismatched mouse cardiac transplantation.
abstract: Although the immunomodulative properties of mesenchymal stem cells (MSCs) open up attractive possibilities in solid-organ transplantation, information concerning the optimal dose, route, timing of administration, major histocompatibility complex (MHC)-restriction and relevant mechanisms is currently lacking. Therefore, better characterization of MSC immunoregulatory activity and elucidation of its mechanisms are crucial. In this study, we confirmed that MSCs did not elicit proliferation by allogeneic CD4(+) T cells, suggesting that MSCs were not immunogenic. By using C57BL/6 mouse MSCs as donor-derived or recipient-derived or as third-party MSCs, we discovered that MSCs suppressed CD4(+) T cell proliferation and prolonged mouse cardiac allograft survival in a dose-dependent and non-MHC-restricted manner. We also found that intraperitoneal administration favored survival prolongation, although this prolongation was weaker than that via the intravenous route. Only infusion at earlier time points favored survival prolongation. Depletion of CD4(+)CD25(+) T cells did not affect the immunosuppression of MSCs on CD4(+) T cells. Moreover, MSCs did not induce regulatory T cells. The in vivo data revealed that MSCs did not increase the percentage of CD4(+)CD25(+) T cells and FoxP3 expression. More importantly, we demonstrated for the first time that depletion of CD4(+)CD25(+) T cells did not hinder MSC-induced survival prolongation, indicating that CD4(+)CD25(+) regulatory T cells were not essential for the prolongation of MSC-mediated allograft survival.
authors.affiliation: Department of Surgery, The Fourth Affiliated Hospital, China Medical University, Shenyang, 110032, Liaoning Province, People's Republic of China, jxf0426@hotmail.com.
authors.forename: Xiaofeng
authors.initials: X
authors.lastname: Jiang
authors.forename: Chen
authors.initials: C
authors.lastname: Liu
authors.forename: Jianpeng
authors.initials: J
authors.lastname: Hao
authors.forename: Dawei
authors.initials: D
authors.lastname: Guo
authors.forename: Jinshuai
authors.initials: J
authors.lastname: Guo
authors.forename: Junchao
authors.initials: J
authors.lastname: Yao
authors.forename: Kun
authors.initials: K
authors.lastname: Jiang
authors.forename: Zheming
authors.initials: Z
authors.lastname: Cui
authors.forename: Lei
authors.initials: L
authors.lastname: Zhu
authors.forename: Wenyu
authors.initials: W
authors.lastname: Sun
authors.forename: Lin
authors.initials: L
authors.lastname: Lin
authors.forename: Jian
authors.initials: J
authors.lastname: Liang
mesh_terms: D064591:Allografts; D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology; D015704:CD4 Antigens / Q000378:metabolism*; D049109:Cell Proliferation; D002469:Cell Separation; D002478:Cells, Cultured; D051858:Forkhead Transcription Factors / Q000378:metabolism; D006085:Graft Survival / Q000276:immunology; D016027:Heart Transplantation; D006650:Histocompatibility Testing; D007165:Immunosuppression Therapy; D053645:Interleukin-2 Receptor alpha Subunit / Q000378:metabolism*; D008212:Lymphocyte Depletion; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000276:immunology*; D051379:Mice; D010641:Phenotype; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000276:immunology*
chemical_list: D015704:CD4 Antigens; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D053645:Interleukin-2 Receptor alpha Subunit