1. Donor and host B7-H4 expression negatively regulates acute graft-versus-host disease lethality
- Author
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Saha, Asim, Taylor, Patricia A, Lees, Christopher J, Panoskaltsis-Mortari, Angela, Osborn, Mark J, Feser, Colby J, Thangavelu, Govindarajan, Melchinger, Wolfgang, Refaeli, Yosef, Hill, Geoffrey R, Munn, David H, Murphy, William J, Serody, Jonathan S, Maillard, Ivan, Kreymborg, Katharina, van den Brink, Marcel, Dong, Chen, Huang, Shuyu, Zang, Xingxing, Allison, James P, Zeiser, Robert, and Blazar, Bruce R
- Subjects
Transplantation ,Stem Cell Research ,Rare Diseases ,Hematology ,Animals ,Bone Marrow Transplantation ,Cell Line ,Tumor ,Cell Proliferation ,Cytokines ,Disease Models ,Animal ,Female ,Gastrointestinal Tract ,Graft vs Host Disease ,Lung ,Lymphoma ,Metabolic Networks and Pathways ,Mice ,Mice ,Inbred BALB C ,Mice ,Inbred C57BL ,Mice ,Knockout ,Oxygen Consumption ,T-Lymphocytes ,Tissue Donors ,Transcriptome ,V-Set Domain-Containing T-Cell Activation Inhibitor 1 ,Bone marrow transplantation ,Immunology ,T cells - Abstract
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.
- Published
- 2019