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

30 Scopus citations

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

ASJC Scopus subject areas

  • Medicine(all)

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    Ni, X., Song, Q., Cassady, K., Deng, R., Jin, H., Zhang, M., Dong, H. M., Forman, S., Martin, P. J., Chen, Y. Z., Wang, J., & 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