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 Transplantation

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 5

Depletion of donor CD4+ T cells protects Paneth cells, colonic epithelial cells, and hepatocytes.

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Depletion of donor CD4+ T cells protects Paneth cells, colonic epithelia...
Lethally irradiated WT BALB/c recipients transplanted with TCD-BM alone or with TCD-BM cells and splenocytes (2.5 × 106) from C57BL/6 donors were injected with rat IgG or anti-CD4 mAb (500 μg/mouse) on day 0. Seven days after HCT, intestinal and liver tissue was analyzed. (A) Small intestine paraffin sections were stained with anti–IL-22R (green), anti-lysozyme (red), and DAPI (blue). (B) Colon paraffin sections were stained with anti-cytokeratin (CK) and DAPI (blue). (A and B) One representative photomicrograph (original magnification, ×400) is shown from 4 per group. (C) Liver enzymes in serum of recipients at days 7, 10, and 21 were measured. Mean ± SEM; n = 4–6 per group (*P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001). ALT, alanine aminotransferase; AST, aspartate amino transferase; ALB, albumin. (D) TUNEL staining for hepatocyte apoptosis assay. A representative immunofluorescent photomicrograph (original magnification, ×400) and mean ± SEM of percentage of TUNEL+ apoptotic hepatocytes are shown; n = 4 per group. (E) Recipients were sacrificed at day 21 after HCT, and sorted liver-infiltrating donor CD8+ T cells (1 × 106) were transplanted together with TCD-BM (5 × 106) into secondary 200-cGy-irradiated Rag2–/– BALB/c mice. Mice were monitored for clinical GVHD. Percentage of body weight change, clinical cutaneous GVHD score, survival curve, and representative photo of mice at day 60 after HCT are shown; n = 8 per group combined from 2 replicate experiments. P values were calculated by 1-way ANOVA multiple-comparisons (C) and multiple t test and log-rank test (E).