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

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 2

Depletion of donor CD4+ T cells preserves GVL effect while preventing GVHD after HCT with A/J donors and C57BL/6 recipients.

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Depletion of donor CD4+ T cells preserves GVL effect while preventing GV...
Lethally irradiated C57BL/6 recipients transplanted with splenocytes (SPL; 10 × 106, 20 × 106, or 40 × 106) and BM cells (10 × 106) from A/J donors. eGFP+ blast-crisis chronic myelogenous leukemia cells (eGFP+ BC-CML, 20 × 103) were injected i.v. on day 0. Recipients were injected with either rat IgG or anti-CD4 mAb (500 μg/mouse) at days 0, 7, 14, 28, 45, and 60 after HCT. Recipients were monitored for signs of tumor burden and clinical GVHD. Data are combined from 2–4 replicate experiments. (A) Percentage of survival; n = 8–16 per group. (B) Moribund mice with or without GVHD during observation and mice at day 100 after HCT were checked for BC-CML tumor cells in the spleen, liver, and BM. Percentage of BC-CML cells in spleen, liver, and BM is shown; n = 6–12 per group. N/D, non-detectable. (C) One hundred days after HCT, splenocytes were stained with anti–H-2Kb, TCRβ, CD4, and CD8 mAbs and analyzed for CD4+ T cell recovery after anti-CD4 mAb treatment. One representative panel from 4 recipients in each group is displayed. (D) Percentage of body weight change in recipients transplanted with 40 × 106 splenocytes treated with either rat IgG or anti-CD4 antibody; n = 8–12 per group. (E) One hundred days after HCT, histopathology of skin, salivary gland, lung, liver (original magnification, ×200), small intestine, and colon (original magnification, ×400) was evaluated. A representative photomicrograph and mean ± SEM of histopathology scores are shown; n = 6 per group. Data represent mean ± SEM combined from 2–4 independent experiments. P values were calculated by log-rank test (A), unpaired 2-tailed Student’s t tests (B and E), or multiple t test (D) (**P < 0.01, ****P < 0.0001). †, indicates all mice died.