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

Xiong Ni, Qingxiao Song, Kaniel Cassady, Ruishu Deng, Hua Jin, Mingfeng Zhang, Haidong M Dong, Stephen Forman, Paul J. Martin, Yuan Zhong Chen, Jianmin Wang, Defu Zeng

Research output: Contribution to journalArticle

26 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)1960-1977
Number of pages18
JournalJournal of Clinical Investigation
Volume127
Issue number5
DOIs
StatePublished - May 1 2017

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Graft vs Host Disease
Ligands
T-Lymphocytes
Transplants
Leukemia
Apoptosis
Cell Transplantation
Lymphoid Tissue
Interleukin-2
Up-Regulation
Tissue Donors
Serum

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Ni, X., Song, Q., Cassady, K., Deng, R., Jin, H., Zhang, M., ... Zeng, D. (2017). PD-L1 interacts with CD80 to regulate graft-versusleukemia activity of donor CD8+ T cells. Journal of Clinical Investigation, 127(5), 1960-1977. https://doi.org/10.1172/JCI91138

PD-L1 interacts with CD80 to regulate graft-versusleukemia activity of donor CD8+ T cells. / Ni, Xiong; Song, Qingxiao; Cassady, Kaniel; Deng, Ruishu; Jin, Hua; Zhang, Mingfeng; Dong, Haidong M; Forman, Stephen; Martin, Paul J.; Chen, Yuan Zhong; Wang, Jianmin; Zeng, Defu.

In: Journal of Clinical Investigation, Vol. 127, No. 5, 01.05.2017, p. 1960-1977.

Research output: Contribution to journalArticle

Ni, X, Song, Q, Cassady, K, Deng, R, Jin, H, Zhang, M, Dong, HM, Forman, S, Martin, PJ, Chen, YZ, Wang, J & Zeng, D 2017, 'PD-L1 interacts with CD80 to regulate graft-versusleukemia activity of donor CD8+ T cells', Journal of Clinical Investigation, vol. 127, no. 5, pp. 1960-1977. https://doi.org/10.1172/JCI91138
Ni, Xiong ; Song, Qingxiao ; Cassady, Kaniel ; Deng, Ruishu ; Jin, Hua ; Zhang, Mingfeng ; Dong, Haidong M ; Forman, Stephen ; Martin, Paul J. ; Chen, Yuan Zhong ; Wang, Jianmin ; Zeng, Defu. / PD-L1 interacts with CD80 to regulate graft-versusleukemia activity of donor CD8+ T cells. In: Journal of Clinical Investigation. 2017 ; Vol. 127, No. 5. pp. 1960-1977.
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