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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 6

Depletion of donor CD4+ T cells augments donor CD8+ T cell apoptosis in the intestine and anergy/exhaustion in the liver, but not in the spleen.

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Depletion of donor CD4+ T cells augments donor CD8+ T cell apoptosis in ...
Lethally irradiated WT BALB/c mice were transplanted and treated at day 0 with IgG or anti-CD4 mAb as in Figure 5. On day 7 after HCT, spleen, liver, and colon from recipients were harvested. (A) Yield, annexin V staining, and BrdU staining of donor CD8+ T cells in spleen, liver, and colon; n = 4–6 per group. (B and C) GRAIL, TIM-3, and IL-7Rα expression by donor CD8+ T cells in spleen and liver; n = 4–6 per group. (D and E) Percentage of EOMES+T-bet+ and EOMES+PD-1+ donor CD8+ T cells in spleen and liver; n = 4 per group. (C and E) Comparison of anti-CD4 treated spleen and liver. Data represent mean ± SEM combined from 2 replicate experiments. P values were calculated by unpaired 2-tailed Student’s t test (*P < 0.05, **P < 0.01, ***P < 0.001).

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

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