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

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

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 3

Depletion of donor CD4+ T cells preserves GVL effect while preventing GVHD in a xenogeneic GVHD model.

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Depletion of donor CD4+ T cells preserves GVL effect while preventing GV...
NSG recipients transplanted with PBMCs (20 × 106 i.p.) from healthy human donors were injected with either IgG or anti–human CD4 mAb (200 μg/mouse, twice weekly for 4 weeks). 1 × 106 eGFP+ Raji cells were injected i.p. on day 0. Recipients were monitored for signs of tumor burden and clinical GVHD. (A) Percentage of body weight change, survival, and representative photograph of mice transplanted with 20 × 106 PBMCs at day 50 to 60 after HCT are shown; n = 12 per group. (B) Histopathology of skin, salivary gland, lung, and liver was evaluated 50–100 days after HCT. Tissues from the IgG-treated group were harvested approximately 50 days after HCT when the recipients had become moribund. Tissues from anti-CD4–treated recipients were harvested at 100 days after HCT when we ended the experiments. A representative photomicrograph (original magnification, ×200) and mean ± SEM of histopathology scores are shown; n = 6 per group. (C) Survival of recipients transplanted with 20 × 106 PBMCs and 1 × 106 Raji cells with IgG or anti–human CD4 mAb; n = 12 per group. Panels show eGFP staining to identify Raji cells in the spleen, liver, and BM with or without anti-CD4 treatment when mice became moribund or at day 100 after HCT when we ended the experiments. Percentages of Raji cells in spleen, liver, and BM are shown; n = 4 per group. Data represent mean ± SEM combined from 2 replicate experiments. P values were calculated by unpaired 2-tailed Student’s t tests (B and C) or multiple t test and log-rank test (A and C) (*P < 0.05, **P < 0.01, ***P < 0.001). †, indicates all mice died.