T-bet Promotes Acute Graft-versus-Host Disease by Regulating Recipient Hematopoietic Cells in Mice. J Immunol 2016 Apr 01;196(7):3168-79
Date
02/24/2016Pubmed ID
26903480Pubmed Central ID
PMC4799777DOI
10.4049/jimmunol.1501020Scopus ID
2-s2.0-84962523010 (requires institutional sign-in at Scopus site) 6 CitationsAbstract
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.
Author List
Fu J, Wu Y, Nguyen H, Heinrichs J, Schutt S, Liu Y, Liu C, Jin J, Anasetti C, Yu XZAuthors
Yongxia Wu PhD Assistant Professor in the Microbiology and Immunology department at Medical College of WisconsinXue-Zhong Yu MD Professor in the Microbiology and Immunology department at Medical College of Wisconsin
MESH terms used to index this publication - Major topics in bold
Acute DiseaseAnimals
Bone Marrow Cells
Bone Marrow Transplantation
Cytokines
Dendritic Cells
Disease Models, Animal
Gene Expression
Graft vs Host Disease
Graft vs Leukemia Effect
Interferon-gamma
Killer Cells, Natural
Liver
Lymphocyte Activation
Mice
Mice, Knockout
Receptors, TNF-Related Apoptosis-Inducing Ligand
Spleen
T-Box Domain Proteins
T-Lymphocytes
TNF-Related Apoptosis-Inducing Ligand
Tissue Donors
Transplantation, Homologous