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PD-L1 interacts with CD80 to regulate graft-versus-leukemia activity of donor CD8+ T cells
Xiong Ni, … , Jianmin Wang, Defu Zeng
Xiong Ni, … , Jianmin Wang, Defu Zeng
Published April 17, 2017
Citation Information: J Clin Invest. 2017;127(5):1960-1977. https://doi.org/10.1172/JCI91138.
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Research Article Immunology Article has an altmetric score of 97

PD-L1 interacts with CD80 to regulate graft-versus-leukemia activity of donor CD8+ T cells

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Abstract

Programmed death ligand-1 (PD-L1) interacts with programmed death-1 (PD-1) and the immunostimulatory molecule CD80 and functions as a checkpoint to regulate immune responses. The interaction of PD-L1 with CD80 alone has been shown to exacerbate the severity of graft-versus-host disease (GVHD), whereas costimulation of CD80 and PD-1 ameliorates GVHD. Here we have demonstrated that temporary depletion of donor CD4+ T cells early after hematopoietic cell transplantation effectively prevents GVHD while preserving strong graft-versus-leukemia (GVL) effects in allogeneic and xenogeneic murine GVHD models. Depletion of donor CD4+ T cells increased serum IFN-γ but reduced IL-2 concentrations, leading to upregulation of PD-L1 expression by recipient tissues and donor CD8+ T cells. In GVHD target tissues, the interactions of PD-L1 with PD-1 on donor CD8+ T cells cause anergy, exhaustion, and apoptosis, thereby preventing GVHD. In lymphoid tissues, the interactions of PD-L1 with CD80 augment CD8+ T cell expansion without increasing anergy, exhaustion, or apoptosis, resulting in strong GVL effects. These results indicate that the outcome of PD-L1–mediated signaling in CD8+ T cells depends on the presence or absence of CD4+ T cells, the nature of the interacting receptor expressed by CD8+ T cells, and the tissue environment in which the signaling occurs.

Authors

Xiong Ni, Qingxiao Song, Kaniel Cassady, Ruishu Deng, Hua Jin, Mingfeng Zhang, Haidong Dong, Stephen Forman, Paul J. Martin, Yuan-Zhong Chen, Jianmin Wang, Defu Zeng

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Figure 1

Three injections of anti-CD4 prevent both acute and chronic GVHD and preserve GVL effects after HCT with C57BL/6 donors and BALB/c recipients.

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Three injections of anti-CD4 prevent both acute and chronic GVHD and pre...
Lethally irradiated BALB/c recipients transplanted with splenocytes (5 × 106) and TCD-BM (2.5 × 106) from C57BL/6 donors. Recipients were challenged with i.p. injection of BCL1/Luc cells (5 × 106 per mouse) and were given 3 i.v. injections of rat IgG or anti-CD4 mAb (500 μg/mouse) at days 0, 14, and 28 after HCT. Recipients given TCD-BM cells (2.5 × 106) alone were used as controls. Mice were monitored for tumor growth using in vivo bioluminescent imaging (BLI), clinical signs of GVHD, and survival. (A) One representative BLI image from each time point is shown for each group. (B) Summary of photons per second of recipients. (C) Clinical GVHD score. (D) Percentage of survival. (E) Serum AST concentrations on days 7 and 12 after HCT. n = 4–8 per group, combined from 2 replicate experiments. Data represent mean ± SEM. P values were calculated by multiple t test (B and C), log-rank test (D), or unpaired 2-tailed Student’s t tests (E) (****P < 0.0001).

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ISSN: 0021-9738 (print), 1558-8238 (online)

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