Donor and host B7-H4 expression negatively regulates acute graft-versus-host disease lethality
Asim Saha, … , Robert Zeiser, Bruce R. Blazar
Asim Saha, … , Robert Zeiser, Bruce R. Blazar
Published October 3, 2019
Citation Information: JCI Insight. 2019;4(19):e127716. https://doi.org/10.1172/jci.insight.127716.
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Research Article Immunology Transplantation

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

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.

Authors

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. Allison, Robert Zeiser, Bruce R. Blazar

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Figure 1

Absence of host B7-H4 expression accelerates GVHD lethality and B7-H4 expression on hematopoietic cells is critical for controlling acute GVHD.

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Absence of host B7-H4 expression accelerates GVHD lethality and B7-H4 ex...
(A–C) Lethally irradiated WT BALB/c recipients or B7-H4–/– recipients were infused with 107 WT B6 BM cells alone or with 1 × 106 WT B6 purified T cells. (A) Kaplan-Meier survival plot represents pooled data (n = 21–30 mice/group) from 3 independent experiments (BM + T cells: WT versus B7-H4–/– recipients; P < 0.0001). (B) Transplanted mice were evaluated for clinical GVHD (n = 8–12/group). BM + T cells: WT versus B7-H4–/– recipients, P < 0.0001 on d7, d14, d17, d21, and d24; P = 0.0009 on d10. Data are representative of 3 independent experiments. (C) Relative weights of transplanted mice. Pooled data (n = 16–22/group) from 2 independent experiments (BM + T cells: WT versus B7-H4–/– recipients; P < 0.05 on d10, d17, d21, and d24. (D) Lethally irradiated WT BALB/c recipients or B7-H4–/– recipients were infused with 107 WT B6 BM cells alone (n = 12 mice) or with 1 × 106 WT B6 purified T cells (n = 18 mice/group) or with 1 × 106 WT B6 CD25-depleted purified T cells (n = 18–20 mice/group). Kaplan-Meier survival plot represents pooled data from 2 independent experiments (BM + T cells: WT versus B7-H4–/– recipients, P < 0.0001; BM + CD25-depleted T cells: WT versus B7-H4–/– recipients, P < 0.0001; WT recipients: BM + T cells versus BM + CD25-depleted T cells, P = 0.016; B7-H4–/– recipients: BM + T cells versus BM + CD25-depleted T cells, P = 0.008. (E) Lethally irradiated WT BALB/c recipients or B7-H4–/– recipients were infused with BM cells from B7-H4–/– or WT BALB/c mice, respectively, to create chimeras. We also created control chimeras (WT→WT). After 3 months, these chimeras were re-irradiated and infused with allogeneic WT B6 BM cells with 2 × 106 WT B6 purified T cells. Kaplan-Meier survival plot of transplanted mice (n = 8–9/group) is shown. WT→WT versus B7-H4–/–→WT chimeras, P = 0.0028; WT→B7-H4–/– versus B7-H4–/–→WT chimeras, P = 0.0141. Data are representative of 2 independent experiments. (B and C) Data represent mean ± SEM. P values were calculated by 2-tailed t test (B and C) or log-rank test (A, D, and E).