Donor and host B7-H4 expression negatively regulates acute graft-versus-host disease lethality
| Autor: | Xingxing Zang, Angela Panoskaltsis-Mortari, Patricia A. Taylor, Jonathan S. Serody, Yosef Refaeli, William J. Murphy, David H. Munn, Shuyu Huang, Marcel R.M. van den Brink, Ivan Maillard, Govindarajan Thangavelu, James P. Allison, Mark J. Osborn, Robert Zeiser, Christopher J. Lees, Chen Dong, Bruce R. Blazar, Geoffrey R. Hill, Asim Saha, Colby J. Feser, Wolfgang Melchinger, Katharina Kreymborg |
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| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Lymphoma T-Lymphocytes Graft vs Host Disease Inbred C57BL Mice 0302 clinical medicine Lung Inbred BALB C Bone Marrow Transplantation Mice Knockout Mice Inbred BALB C Tumor General Medicine Hematology Tissue Donors Haematopoiesis medicine.anatomical_structure 030220 oncology & carcinogenesis Cytokines Female Metabolic Networks and Pathways Research Article Bone marrow transplantation T cell Knockout Immunology T cells Biology Proinflammatory cytokine Cell Line 03 medical and health sciences Chimera (genetics) Oxygen Consumption Rare Diseases Cell Line Tumor medicine Animals Cell Proliferation Transplantation Animal V-Set Domain-Containing T-Cell Activation Inhibitor 1 Stem Cell Research Mice Inbred C57BL Gastrointestinal Tract Cytolysis Disease Models Animal 030104 developmental biology Apoptosis Disease Models Cancer research Transcriptome Homing (hematopoietic) |
| Zdroj: | JCI insight, vol 4, iss 19 |
| Popis: | B7-H4 is a negative regulatory B7 family member. We investigated the role of host and donor B7-H4 in regulating acute graft-versus-host disease (GVHD). Allogeneic donor T cells infused into B7-H4(–/–) versus WT recipients markedly accelerated GVHD-induced lethality. Chimera studies pointed toward B7-H4 expression on host hematopoietic cells as more critical than parenchymal cells in controlling GVHD. Rapid mortality in B7-H4(–/–) recipients was associated with increased donor T cell expansion, gut T cell homing and loss of intestinal epithelial integrity, increased T effector function (proliferation, proinflammatory cytokines, cytolytic molecules), and reduced apoptosis. Higher metabolic demands of rapidly proliferating donor T cells in B7-H4(–/–) versus WT recipients required multiple metabolic pathways, increased extracellular acidification rates (ECARs) and oxygen consumption rates (OCRs), and increased expression of fuel substrate transporters. During GVHD, B7-H4 expression was upregulated on allogeneic WT donor T cells. B7-H4(–/–) donor T cells given to WT recipients increased GVHD mortality and had function and biological properties similar to WT T cells from allogeneic B7-H4(–/–) recipients. Graft-versus-leukemia responses were intact regardless as to whether B7-H4(–/–) mice were used as hosts or donors. Taken together, these data provide new insights into the negative regulatory processes that control GVHD and provide support for developing therapeutic strategies directed toward the B7-H4 pathway. |
| Databáze: | OpenAIRE |
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