TY - JOUR
T1 - Donor and host B7-H4 expression negatively regulates acute graft-versus-host disease lethality
AU - Saha, Asim
AU - Taylor, Patricia A.
AU - Lees, Christopher J.
AU - Panoskaltsis-Mortari, Angela
AU - Osborn, Mark J.
AU - Feser, Colby J.
AU - Thangavelu, Govindarajan
AU - Melchinger, Wolfgang
AU - Refaeli, Yosef
AU - Hill, Geoffrey R.
AU - Munn, David H.
AU - Murphy, William J.
AU - Serody, Jonathan S.
AU - Maillard, Ivan
AU - Kreymborg, Katharina
AU - van den Brink, Marcel
AU - Dong, Chen
AU - Huang, Shuyu
AU - Zang, Xingxing
AU - Allison, James P.
AU - Zeiser, Robert
AU - Blazar, Bruce R.
N1 - Publisher Copyright:
© 2019, American Society for Clinical Investigation.
PY - 2019
Y1 - 2019
N2 - 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.
AB - 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.
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U2 - 10.1172/jci.insight.127716
DO - 10.1172/jci.insight.127716
M3 - Article
C2 - 31578305
AN - SCOPUS:85072982118
SN - 2379-3708
VL - 4
JO - JCI Insight
JF - JCI Insight
IS - 19
M1 - e127716
ER -