B7H1/CD80 interaction augments PD-1-dependent T Cell apoptosis and ameliorates graft-versus-host disease

Ruishu Deng, Kaniel Cassady, Xiaofan Li, Sheng Yao, Mingfeng Zhang, Jeremy Racine, Jeffrey Lin, Lieping Chen, Defu Zeng

Research output: Contribution to journalArticlepeer-review

Abstract

Interactions of B7H1 (programmed death ligand 1 [PD-L1]) with its two ligands, PD-1 and CD80, on T cells play a pivotal role in controlling T cell activation, proliferation, anergy, and apoptosis. However, the interactions between the two pathways remain unknown. Using an alloimmune response model of graft-versus-host disease (GVHD), we report in this study that: 1) Comparison of proliferation and apoptosis of wild-type (WT) and PD-1-/-CD4+ conventional T (Tcon) cells in WT and B7H1-/- recipients revealed that B7H1/CD80 interaction per se augments T cell proliferation, and this interaction augments T cell apoptosis mediated by B7H1/PD-1 interaction. This observation was recapitulated in an in vitro MLR assay. 2) Specific blockade of the B7H1/CD80 axis by anti-B7H1 mAb reduces WT-alloreactive Tcon cell proliferation, IL-2 production, expression of PD-1, and apoptosis, resulting in worsening GVHD. In contrast, specific blockade of B7H1/CD80 interaction reduces donor PD-1-/- Tcon cell proliferation without an impact on apoptosis, resulting in ameliorating GVHD. 3) B7H1 fused to an Ig Fc domain (B7H1-Ig), when produced in vivo by hydrodynamic injection of B7H1-Ig plasmid, ameliorates GVHD by augmenting proliferation and apoptosis of WT- Alloreactive Tcon cells. Conversely, B7H1-Ig treatment has no impact on apoptosis but augments PD-1-/- T cell proliferation and worsens GVHD. These results indicate that B7H1/CD80 interaction augments Tcon cell proliferation, IL-2 production, and expression of PD-1, which leads to increased apoptosis mediated by the B7H1/PD-1 pathway. Additionally, by engaging both PD-1 and CD80, B7H1-Ig can be a powerful therapeutic reagent for downregulating the T cell immune response.

Original languageEnglish (US)
Pages (from-to)560-574
Number of pages15
JournalJournal of Immunology
Volume194
Issue number2
DOIs
StatePublished - Jan 15 2015
Externally publishedYes

ASJC Scopus subject areas

  • Immunology

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