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. Allison, Robert Zeiser, Bruce R. Blazar
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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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 5

B7-H4–/– donor T cells cause increased GVHD lethality that is independent of donor Treg function.

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B7-H4–/– donor T cells cause increased GVHD lethality that is independen...
(A and B) Lethally irradiated B6 or BALB/c recipients were infused with 107 WT B6 BM cells plus 2 × 106 B6 Ly5.2 (CD45.1+) T cells. Mice were sacrificed (n = 4–5/group/day) on day 3, day 5, and day 7 after BMT, and splenic donor CD4+ (A) and CD8+ (B) T cells were analyzed by flow cytometry for B7-H4 expression. Data are representative of 2 independent experiments. (C) Lethally irradiated B6 recipients were infused with 107 WT BALB/c BM cells plus 2 × 106 WT BALB/c or B7-H4–/– T cells. Mice were sacrificed on day 5 after BMT, and splenic donor CD4+ and CD8+ T cells were analyzed by flow cytometry for B7-H4 expression. Pooled data from 2 independent experiments (n = 8–10/group). (D and E) Lethally irradiated B6 recipients were infused with 107 WT BALB/c BM cells alone or with 2 × 106 WT BALB/c or B7-H4–/– T cells. (D) Kaplan-Meier survival plot represents pooled data from 3 independent experiments (n = 21–29/group; BM + T cells: recipients of WT versus B7-H4–/– donor T cells, P < 0.0001). (E) Transplanted mice were evaluated for clinical GVHD. BM + T cells: recipients of WT versus B7-H4–/– donor T cells, P < 0.0001 on d7, d15, d18, d22, d25, d29, d32, and d39; P = 0.0043 on d11. Pooled data from 2 independent experiments (n = 13–19/group). (F) Lethally irradiated B6 recipients were infused with 107 WT BALB/c BM cells alone or with 2 × 106 WT BALB/c or B7-H4–/– CD25-depleted T cells. Kaplan-Meier survival plot represents pooled data from 2 independent experiments (n = 14–21/group; BM + T cells: recipients of WT versus B7-H4–/– donor T cells, P < 0.0001). (G) Lethally irradiated B6 recipients were infused with 107 WT BALB/c BM cells alone, or with 2.5 × 106 WT BALB/c T cells, or with 2.5 × 106 WT BALB/c T cells plus 1.25 × 106 WT BALB/c Tregs or 1.25 × 106 B7-H4–/– Tregs. Kaplan-Meier survival plot represents pooled data from 2 independent experiments (n = 13–20/group; WT T cells versus WT T cells + WT Tregs, P = 0.0001; WT T cells versus WT T cells + B7-H4–/– Tregs, P < 0.0001; WT T cells + WT Tregs versus WT T cells + B7-H4–/– Tregs, P = 0.1732). (A–C and E) Data represent mean ± SEM. P values were calculated by 2-tailed t test (A–C and E) or log-rank test (D, F, and G).