title: DR3 signaling modulates the function of Foxp3+ regulatory T cells and the severity of acute graft-versus-host disease.
abstract: CD4+Foxp3+regulatory T cells (Treg) are a subpopulation of T cells, which regulate the immune system and enhance immune tolerance after transplantation. Donor-derived Treg prevent the development of lethal acute graft-versus-host disease (GVHD) in murine models of allogeneic hematopoietic stem cell transplantation. We recently demonstrated that a single treatment of the agonistic antibody to DR3 (death receptor 3, αDR3) to donor mice resulted in the expansion of donor-derived Treg and prevented acute GVHD, although the precise role of DR3 signaling in GVHD has not been elucidated. In this study, we comprehensively analyzed the immunophenotype of Treg after DR3 signal activation, demonstrating that DR3-activated Treg (DR3-Treg) had an activated/mature phenotype. Furthermore, the CD25+Foxp3+subpopulation in DR3-Treg showed stronger suppressive effects in vivo. Prophylactic treatment of αDR3 to recipient mice expanded recipient-derived Treg and reduced the severity of GVHD, whereas DR3 activation in mice with ongoing GVHD further promoted donor T-cell activation/proliferation. These data suggest that the function of DR3 signaling was highly dependent on the activation status of the T cells. In conclusion, our data demonstrated that DR3 signaling affects the function of Treg and T-cell activation after alloantigen exposure in a time-dependent manner. These observations provide important information for future clinical testing using human DR3 signal modulation and highlight the critical effect of the state of T-cell activation on clinical outcomes after activation of DR3.
authors.affiliation: Division of Blood and Marrow Transplantation, Stanford University, Stanford, CA.|Department of Hematology, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan.
authors.forename: Hidekazu
authors.identifier: 0000-0002-6277-4082
authors.initials: H
authors.lastname: Nishikii
authors.affiliation: Division of Blood and Marrow Transplantation, Stanford University, Stanford, CA.
authors.forename: Byung-Su
authors.initials: BS
authors.lastname: Kim
authors.affiliation: Department of Hematology, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan.
authors.forename: Yasuhisa
authors.initials: Y
authors.lastname: Yokoyama
authors.affiliation: Division of Blood and Marrow Transplantation, Stanford University, Stanford, CA.|Department of Hematology, Central South University Xiangya Hospital, Changsha, China; and.
authors.forename: Yan
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Division of Blood and Marrow Transplantation, Stanford University, Stanford, CA.
authors.forename: Jeanette
authors.initials: J
authors.lastname: Baker
authors.affiliation: Division of Blood and Marrow Transplantation, Stanford University, Stanford, CA.
authors.forename: Antonio
authors.initials: A
authors.lastname: Pierini
authors.affiliation: Division of Blood and Marrow Transplantation, Stanford University, Stanford, CA.
authors.forename: Maite
authors.initials: M
authors.lastname: Alvarez
authors.affiliation: Divisions of Hematology/Oncology and Stem Cell Transplantation and Regenerative Medicine, Department of Pediatrics, Stanford University, Stanford, CA.
authors.forename: Melissa
authors.initials: M
authors.lastname: Mavers
authors.affiliation: Division of Blood and Marrow Transplantation, Stanford University, Stanford, CA.
authors.forename: Kristina
authors.initials: K
authors.lastname: Maas-Bauer
authors.affiliation: Division of Blood and Marrow Transplantation, Stanford University, Stanford, CA.
authors.forename: Yuqiong
authors.initials: Y
authors.lastname: Pan
authors.affiliation: Department of Hematology, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan.
authors.forename: Shigeru
authors.initials: S
authors.lastname: Chiba
authors.affiliation: Division of Blood and Marrow Transplantation, Stanford University, Stanford, CA.
authors.forename: Robert S
authors.initials: RS
authors.lastname: Negrin
mesh_terms: D000208:Acute Disease; D000818:Animals; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D020869:Gene Expression Profiling; D006086:Graft vs Host Disease / Q000235:genetics / Q000276:immunology* / Q000517:prevention & control; D016130:Immunophenotyping; D053645:Interleukin-2 Receptor alpha Subunit / Q000378:metabolism; D007519:Isoantigens / Q000276:immunology; D008213:Lymphocyte Activation / Q000276:immunology; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D053219:Receptors, Tumor Necrosis Factor, Member 25 / Q000378:metabolism*; D015398:Signal Transduction; D050378:T-Lymphocytes, Regulatory / Q000276:immunology; D014184:Transplantation, Homologous
chemical_list: D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D053645:Interleukin-2 Receptor alpha Subunit; D007519:Isoantigens; D053219:Receptors, Tumor Necrosis Factor, Member 25