Abstract
There is increasing evidence that interaction between programmed death 1 (PD-1) and its ligands PD-1 (PD-L1) plays a critical role in the pathology of acute graft-versus-host disease (aGVHD). However, the role of PD-L1 in the development of aGVHD has been controversial in recent mouse studies. In this study, we carried out studies in a murine aGVHD model to clarify the role of PD-L1 in aGVHD pathogenesis. We found that systemic overexpression of PD-L1 by hydrodynamic gene transfer (HGT) method in vivo ameliorates aGVHD-induced lethality in mice. Systemic overexpression of PD-L1 inhibits the donor T cells activation, effector memory status, as well as Th1 and Th17 cells responses in vivo. In addition, PD-L1 Ig treatment significantly suppressed T cells’ proliferation, promoted T cells’ apoptosis, and reduced pro-inflammatory cytokines expression by effector T cells in vitro in the stimulation of anti-CD3/CD28 and allogeneic dendritic cells. However, we found that PD-L1 overexpression did not affect Treg cells’ differentiation in vivo and in vitro, depletion of Treg cells in PD-L1 HGT recipients did not aggravate aGVHD mortality. Therefore, our results demonstrated that systemic treatment with PD-L1 protein ameliorates aGVHD by suppressing effector but not regulatory T cell function. Our findings suggest that systemic treatment with PD-L1 may be a potential strategy to prevent or ameliorate aGVHD.
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Acknowledgements
This work was supported by the grants from National Natural Science Foundation of China (81500145, 81570138, 81700173), Suzhou Science and Technology Development Plan (sys2018027). The Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD). The Innovation Capability Development Project of Jiangsu Province (No. BM2015004). The National Key Research and Development Program of China (2016YFC0902800, 2017YFA0104502, 2017ZX09304021), Jiangsu Provincial Key Medical Center (YXZXA2016002).
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AS, DW and SM designed the study; LT and SM performed the experiments; HG, JW and YX contributed to the experiments; LT and SM analyzed the data and wrote the manuscript. All authors have discussed and revised the manuscript.
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All animal experiments were carried out and approved according to the guidelines of the animal care and use committee at Soochow University.
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5_2019_539_MOESM1_ESM.tif
Fig. Suppl 1. Immunophenotyping of systemic overexpression of PD-L1 in normal mice. (A) PD-L1 overexpressing plasmid or vector control plasmid were injected into mice by hydrodynamic gene transfer (HGT), the liver sections were immunohistochemically stained with anti-PD-L1 antibody at day 2 after HGT. Original magnification ×200. (B–D) Splenocytes were obtained from mice on day 2 after HGT (n=3 per group) and analyzed by flow cytometry. (B) CD3+T, CD4+T, and CD8+T cells, (C) activated CD3+T (CD3+CD69+ subset), activated CD4+T (CD4+CD69+ subset), activated CD8+T cells (CD8+CD69+ subset), (D) naive (CD62–CD44+ subset), effector (CD62–CD44+ subset) and memory cells CD62–CD44+ subset) in CD3+T, CD4+T, and CD8+T subsets (E) Treg cells and IFN-γ, TNF-α and IL-17 production by CD4+ cells. Data shown are mean ± SD (TIF 2090 KB)
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Tang, L., Ma, S., Gong, H. et al. PD-L1 Ameliorates Murine Acute Graft-Versus-Host Disease by Suppressing Effector But Not Regulatory T Cells Function. Arch. Immunol. Ther. Exp. 67, 179–187 (2019). https://doi.org/10.1007/s00005-019-00539-4
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DOI: https://doi.org/10.1007/s00005-019-00539-4