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

J Immunol. 2015 Jan 15;194(2):560-74. doi: 10.4049/jimmunol.1402157. Epub 2014 Dec 8.

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Apoptosis / genetics
  • Apoptosis / immunology*
  • B7-1 Antigen / genetics
  • B7-1 Antigen / immunology*
  • B7-H1 Antigen / genetics
  • B7-H1 Antigen / immunology*
  • B7-H1 Antigen / pharmacology
  • CD4-Positive T-Lymphocytes / immunology*
  • CD4-Positive T-Lymphocytes / pathology
  • Cell Proliferation / genetics
  • Gene Expression Regulation / drug effects
  • Gene Expression Regulation / genetics
  • Gene Expression Regulation / immunology
  • Graft vs Host Disease / genetics
  • Graft vs Host Disease / immunology*
  • Graft vs Host Disease / pathology
  • Graft vs Host Disease / therapy
  • Interleukin-2 / genetics
  • Interleukin-2 / immunology
  • Mice
  • Mice, Inbred BALB C
  • Mice, Knockout
  • Programmed Cell Death 1 Receptor / genetics
  • Programmed Cell Death 1 Receptor / immunology*
  • Recombinant Fusion Proteins / genetics
  • Recombinant Fusion Proteins / immunology
  • Recombinant Fusion Proteins / pharmacology

Substances

  • B7-1 Antigen
  • B7-H1 Antigen
  • Interleukin-2
  • Pdcd1 protein, mouse
  • Programmed Cell Death 1 Receptor
  • Recombinant Fusion Proteins