title: Host Foxp3+CD4+ Regulatory T Cells Act as a Negative Regulator of Dendritic Cells in the Peritransplantation Period.
abstract: Host Foxp3+CD4+ regulatory T cells (Tregs) have been shown to suppress graft-versus-host disease (GVHD) in experimental bone marrow transplantation (BMT) models; however, the detailed mechanism is unknown. To address this issue, we established a murine MHC-haploidentical BMT model (BDF1 (H-2b/d) → B6C3F1 (H-2b/k)), in which transplantation following conditioning with high-dose (13 Gy) or low-dose (5 Gy) total body irradiation corresponds to myeloablative stem cell transplantation (MAST) or reduced-intensity stem cell transplantation (RIST) BMT. All MAST recipients died of GVHD within 70 d, whereas RIST recipients developed almost no GVHD and survived for at least 3 mo. In this BMT model, we investigated the kinetics of immune cells in the mesenteric lymph nodes because GVHD was most prominent in the intestines. Host Tregs that survived after total body irradiation could proliferate transiently by day 4. Comparing the kinetics of immune cells among MAST, RIST, and anti-CD25 mAb-treated RIST, we found that the transiently surviving host Tregs were fully functional, closely contacted with host dendritic cells (DCs), and significantly restrained the maturation (CD80 and CD86 expression) of DCs in a dose-dependent manner. There was a positive correlation between the ratio of DCs to host Tregs and the extent of maturation of DCs. Host Tregs suppressed alloresponse mainly by contact inhibition. Host Tregs are already active in lymph nodes before transplantation and restrain the maturation of host DCs, thereby dampening the ability of DCs to activate allogeneic donor T cells and consequently reducing the magnitude of graft-versus-host reaction. Thus, host Tregs are negative regulators of host DCs that act in the peritransplantation period.
authors.affiliation: Division of Hematology, Department of Internal Medicine, Hyogo College of Medicine, Hyogo 663-8501, Japan; and.
authors.forename: Takayuki
authors.initials: T
authors.lastname: Inoue
authors.affiliation: Division of Hematology, Department of Internal Medicine, Hyogo College of Medicine, Hyogo 663-8501, Japan; and.
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Ikegame
authors.affiliation: Division of Hematology, Department of Internal Medicine, Hyogo College of Medicine, Hyogo 663-8501, Japan; and.
authors.forename: Katsuji
authors.initials: K
authors.lastname: Kaida
authors.affiliation: Division of Hematology, Department of Internal Medicine, Hyogo College of Medicine, Hyogo 663-8501, Japan; and.
authors.forename: Masaya
authors.initials: M
authors.lastname: Okada
authors.affiliation: Division of Hematology, Department of Internal Medicine, Hyogo College of Medicine, Hyogo 663-8501, Japan; and.
authors.forename: Satoshi
authors.identifier: http://orcid.org/0000-0002-8537-2422
authors.initials: S
authors.lastname: Yoshihara
authors.affiliation: Division of Hematology, Department of Internal Medicine, Hyogo College of Medicine, Hyogo 663-8501, Japan; and.
authors.forename: Hiroya
authors.initials: H
authors.lastname: Tamaki
authors.affiliation: Department of Transfusion Medicine, Hyogo College of Medicine, Hyogo 663-8501, Japan.
authors.forename: Yoshihiro
authors.identifier: http://orcid.org/0000-0003-4008-2613
authors.initials: Y
authors.lastname: Fujimori
authors.affiliation: Division of Hematology, Department of Internal Medicine, Hyogo College of Medicine, Hyogo 663-8501, Japan; and.
authors.forename: Toshihiro
authors.identifier: http://orcid.org/0000-0003-0101-8088
authors.initials: T
authors.lastname: Soma
authors.affiliation: Division of Hematology, Department of Internal Medicine, Hyogo College of Medicine, Hyogo 663-8501, Japan; and ogawah@hyo-med.ac.jp.
authors.forename: Hiroyasu
authors.initials: H
authors.lastname: Ogawa
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D016026:Bone Marrow Transplantation; D015704:CD4 Antigens / Q000378:metabolism; D002454:Cell Differentiation; D049109:Cell Proliferation; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology*; D005260:Female; D051858:Forkhead Transcription Factors / Q000378:metabolism; D006086:Graft vs Host Disease / Q000276:immunology*; D008198:Lymph Nodes / Q000166:cytology / Q000276:immunology; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D033581:Stem Cell Transplantation; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000276:immunology* / Q000637:transplantation*; D014184:Transplantation, Homologous
chemical_list: D015704:CD4 Antigens; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse