title: T-bet Promotes Acute Graft-versus-Host Disease by Regulating Recipient Hematopoietic Cells in Mice.
abstract: Beyond its critical role in T cells, T-bet regulates the functions of APCs including dendritic cells and B cells, as well as NK cells. Given that recipient APCs are essential for priming allogeneic T cells and recipient NK or T cells are able to reject allogeneic donor cells, we evaluated the role of T-bet on the host in acute graft-versus-host disease (GVHD) using murine models of allogeneic bone marrow transplantation. T-bet(-/-) recipients developed significantly milder GVHD than their wild type counterparts in MHC-mismatched or CD4-dependent minor histocompatibility Ag-mismatched models. Allogeneic donor T cells, in particular, CD4 subset, significantly reduced IFN-γ production, proliferation and migration, and caused less injury in liver and gut of T-bet(-/-) recipients. We further observed that T-bet on recipient hematopoietic cells was primarily responsible for the donor T cell response and pathogenicity in GVHD. T-bet(-/-) dendritic cells expressed higher levels of Trail, whereas they produced lower levels of IFN-γ and IL-12/23 p40, as well as chemokine CXCL9, resulting in significantly higher levels of apoptosis, less priming, and infiltration of donor T cells. Meanwhile, NK cells in T-bet(-/-) hosts partially contribute to the decreased donor T cell proliferation. Furthermore, although T-bet on hematopoietic cells was required for GVHD development, it was largely dispensable for the graft-versus-leukemia effect. Taken together with our previous findings, we propose that T-bet is a potential therapeutic target for the control of GVHD through regulating donor T cells and recipient hematopoietic cells.
authors.affiliation: Cancer Biology Ph.D. Program, University of South Florida, Tampa, FL 33612; Department of Immunology, Blood and Marrow Transplantation, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612; Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC 29425;
authors.forename: Jianing
authors.identifier: http://orcid.org/0000-0003-1500-5405
authors.initials: J
authors.lastname: Fu
authors.affiliation: Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC 29425;
authors.forename: Yongxia
authors.initials: Y
authors.lastname: Wu
authors.affiliation: Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC 29425;
authors.forename: Hung
authors.identifier: http://orcid.org/0000-0001-9416-5137
authors.initials: H
authors.lastname: Nguyen
authors.affiliation: Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC 29425;
authors.forename: Jessica
authors.initials: J
authors.lastname: Heinrichs
authors.affiliation: Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC 29425;
authors.forename: Steven
authors.initials: S
authors.lastname: Schutt
authors.affiliation: Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC 29425;
authors.forename: Yuejun
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Pathology, Immunology and Laboratory Medicine, University of Florida, Gainesville, FL 32611;
authors.forename: Chen
authors.initials: C
authors.lastname: Liu
authors.affiliation: Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC 29425; Laboratory of Hepatobiliary and Pancreatic Surgery, Affiliated Hospital of Guilin Medical University, Guilin, 541001 Guangxi, China; and.
authors.forename: Junfei
authors.initials: J
authors.lastname: Jin
authors.affiliation: Department of Immunology, Blood and Marrow Transplantation, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612;
authors.forename: Claudio
authors.initials: C
authors.lastname: Anasetti
authors.affiliation: Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC 29425; Department of Medicine, Medical University of South Carolina, Charleston, SC 29425 yux@musc.edu.
authors.forename: Xue-Zhong
authors.initials: XZ
authors.lastname: Yu
mesh_terms: D000208:Acute Disease; D000818:Animals; D001854:Bone Marrow Cells / Q000378:metabolism*; D016026:Bone Marrow Transplantation; D016207:Cytokines / Q000378:metabolism; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism; D004195:Disease Models, Animal; D015870:Gene Expression; D006086:Graft vs Host Disease / Q000209:etiology* / Q000378:metabolism*; D020544:Graft vs Leukemia Effect / Q000235:genetics / Q000276:immunology; D007371:Interferon-gamma / Q000096:biosynthesis; D007694:Killer Cells, Natural / Q000276:immunology / Q000378:metabolism; D008099:Liver / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008213:Lymphocyte Activation / Q000235:genetics / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism; D013154:Spleen / Q000276:immunology; D020825:T-Box Domain Proteins / Q000235:genetics* / Q000378:metabolism*; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000235:genetics / Q000378:metabolism; D014019:Tissue Donors; D014184:Transplantation, Homologous; D000098815:T-bet Transcription Factor
chemical_list: D016207:Cytokines; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor; D053221:TNF-Related Apoptosis-Inducing Ligand; D007371:Interferon-gamma