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.
View: Text | PDF
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

×

Figure 3

Absence of B7-H4 expression on host cells increases donor T cell effector function that promotes increased gut injury in recipients.

Options: View larger image (or click on image) Download as PowerPoint
Absence of B7-H4 expression on host cells increases donor T cell effecto...
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) Mice were sacrificed (n = 5–7/group) on day 21 after BMT, and H&E-stained tissue sections were scored for GVHD. (B) FITC-dextran was administered orally on day 22 after BMT (n = 8–10 mice/group), and plasma levels were measured after 4 hours. (C–K) Mice were sacrificed on day 23 after BMT (n = 10/group), and lymphocytes isolated from the colon (2 colons were pooled to make 1 pooled sample and 5 pooled samples per group) were analyzed by flow cytometry. Donor CD4+ and CD8+ T cells were analyzed for total cell numbers (C), and surface expression of CXCR3 (E), CCR5 (F), or CCR9 (G). Donor T cells were also analyzed for intracellular expression of Ki-67 (D), Granzyme B (H), IFN-γ (I), TNF-α (J), or IL-6 (K). (A–K) Data are representative of 2 independent experiments. Data represent mean ± SEM. P values were calculated by 2-tailed t test. *P < 0.05; **P < 0.01; ***P < 0.001; ****P < 0.0001.