title: T-bet is critical for the development of acute graft-versus-host disease through controlling T cell differentiation and function.
abstract: T-bet is a master regulator for IFN-γ production and Th1 differentiation. We evaluated the roles of T-bet and IFN-γ in T cell responses in acute graft-versus-host disease (GVHD) and found that T-bet(-/-) T cells induced significantly less GVHD compared with wild-type or IFN-γ(-/-) counterparts in both MHC-mismatched and MHC-matched but minor histocompatibility Ag-mismatched models driven by CD4 T cells. T-bet(-/-), but not IFN-γ(-/-), CD4 T cells had a markedly reduced ability to cause tissue damage in liver and gut. This distinct outcome is reflected by the differential gene expression on donor CD4 T cells deficient for T-bet or IFN-γ. At mRNA and protein levels, we defined several T-bet-dependent molecules that may account for the impaired ability of T-bet(-/-) T cells to migrate into target organs and to produce Th1-related cytokines. Moreover, these molecules were independent of either endogenous IFN-γ, such as CXCR3 and programmed death-1, or systematic IFN-γ, such as NKG2D, I-A(b), and granzyme B. Although both T-bet(-/-) and IFN-γ(-/-) CD4 T cells are prone to differentiate into Th17 cells, polarized Th17 cells deficient for T-bet but not for IFN-γ had a significantly reduced ability to cause GVHD. Finally, T-bet(-/-) T cells had a compromised graft-versus-leukemia effect, which could be essentially reversed by neutralization of IL-17 in the recipients. We conclude that T-bet is required for Th1 differentiation and migration, as well as for optimal function of Th17 cells. Thus, targeting T-bet or regulating its downstream effectors independent of IFN-γ may be a promising strategy to control GVHD in the clinic.
authors.affiliation: Cancer Biology Ph.D. Program, University of South Florida, Tampa, FL 33612; 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.initials: J
authors.lastname: Fu
authors.affiliation: Immunology, Blood and Marrow Transplantation, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612;
authors.forename: Dapeng
authors.initials: D
authors.lastname: Wang
authors.affiliation: Immunology, Blood and Marrow Transplantation, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612;
authors.forename: Yu
authors.initials: Y
authors.lastname: Yu
authors.affiliation: Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC 29425; Department of Pathology and Cell Biology, University of South Florida, Tampa, FL 33612;
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: Yongxia
authors.initials: Y
authors.lastname: Wu
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: Immunology, Blood and Marrow Transplantation, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612;
authors.forename: Kane
authors.initials: K
authors.lastname: Kaosaard
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: Immunology, Blood and Marrow Transplantation, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612;
authors.forename: Kelley
authors.initials: K
authors.lastname: Haarberg
authors.affiliation: Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC 29425;
authors.forename: David
authors.initials: D
authors.lastname: Bastian
authors.affiliation: Department of Radiation Oncology, Medical University of South Carolina, Charleston, SC 29425; and.
authors.forename: Daniel G
authors.initials: DG
authors.lastname: McDonald
authors.affiliation: 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: D000818:Animals; D002454:Cell Differentiation / Q000276:immunology; D002465:Cell Movement / Q000235:genetics / Q000276:immunology; D005786:Gene Expression Regulation / Q000276:immunology; D006086:Graft vs Host Disease / Q000276:immunology*; D053804:Granzymes / Q000096:biosynthesis; D000949:Histocompatibility Antigens Class II / Q000096:biosynthesis; D007371:Interferon-gamma / Q000235:genetics*; D020381:Interleukin-17 / Q000037:antagonists & inhibitors; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D055655:NK Cell Lectin-Like Receptor Subfamily K / Q000096:biosynthesis; D061026:Programmed Cell Death 1 Receptor / Q000096:biosynthesis; D012333:RNA, Messenger / Q000235:genetics; D054367:Receptors, CXCR3 / Q000096:biosynthesis; D017471:Receptors, Interferon / Q000096:biosynthesis / Q000235:genetics; D020825:T-Box Domain Proteins / Q000235:genetics*; D018417:Th1 Cells / Q000166:cytology / Q000276:immunology*; D058504:Th17 Cells / Q000166:cytology / Q000276:immunology*; D000096743:Interferon gamma Receptor; D000098815:T-bet Transcription Factor
chemical_list: D053804:Granzymes; D000949:Histocompatibility Antigens Class II; D007371:Interferon-gamma; D020381:Interleukin-17; D055655:NK Cell Lectin-Like Receptor Subfamily K; D061026:Programmed Cell Death 1 Receptor; D012333:RNA, Messenger; D054367:Receptors, CXCR3; D017471:Receptors, Interferon; D020825:T-Box Domain Proteins; D000096743:Interferon gamma Receptor; D000098815:T-bet Transcription Factor; C515188:Cxcr3 protein, mouse; C474482:I-A(b) antigen, mouse; C527086:Klrk1 protein, mouse; C491383:Pdcd1 protein, mouse; C509214:Gzmb protein, mouse