Donor and host B7-H4 expression negatively regulates acute graft-versus-host disease lethality

Asim Saha, Patricia A. Taylor, Christopher J Lees, Angela Panoskaltsis-Mortari, Mark J Osborn, Colby J. Feser, Govindarajan Thangavelu, Wolfgang Melchinger, Yosef Refaeli, Geoffrey R. Hill, David H. Munn, William J. Murphy, Jonathan S. Serody, Ivan Maillard, Katharina Kreymborg, Marcel van den Brink, Chen Dong, Shuyu Huang, Xingxing Zang, James P. AllisonRobert Zeiser, Bruce R Blazar

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Article numbere127716
JournalJCI Insight
Volume4
Issue number19
DOIs
StatePublished - Jan 1 2019

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Graft vs Host Disease
T-Lymphocytes
Mortality
Metabolic Networks and Pathways
Oxygen Consumption
Leukemia
Apoptosis
Cytokines
Transplants

PubMed: MeSH publication types

  • Journal Article

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Donor and host B7-H4 expression negatively regulates acute graft-versus-host disease lethality. / 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; Blazar, Bruce R.

In: JCI Insight, Vol. 4, No. 19, e127716, 01.01.2019.

Research output: Contribution to journalArticle

Saha, A, Taylor, PA, Lees, CJ, Panoskaltsis-Mortari, A, Osborn, MJ, Feser, CJ, Thangavelu, G, Melchinger, W, Refaeli, Y, Hill, GR, Munn, DH, Murphy, WJ, Serody, JS, Maillard, I, Kreymborg, K, van den Brink, M, Dong, C, Huang, S, Zang, X, Allison, JP, Zeiser, R & Blazar, BR 2019, 'Donor and host B7-H4 expression negatively regulates acute graft-versus-host disease lethality', JCI Insight, vol. 4, no. 19, e127716. https://doi.org/10.1172/jci.insight.127716
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 ; Blazar, Bruce R. / Donor and host B7-H4 expression negatively regulates acute graft-versus-host disease lethality. In: JCI Insight. 2019 ; Vol. 4, No. 19.
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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.",
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AU - Saha, Asim

AU - Taylor, Patricia A.

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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

PY - 2019/1/1

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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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