Blockade of B7-H1 on macrophages suppresses CD4+ T cell proliferation by augmenting IFN-gamma-induced nitric oxide production

J Immunol. 2005 Aug 1;175(3):1586-92. doi: 10.4049/jimmunol.175.3.1586.

Abstract

PD-1 is an immunoinhibitory receptor that belongs to the CD28/CTLA-4 family. B7-H1 (PD-L1) and B7-DC (PD-L2), which belong to the B7 family, have been identified as ligands for PD-1. Paradoxically, it has been reported that both B7-H1 and B7-DC co-stimulate or inhibit T cell proliferation and cytokine production. To determine the role of B7-H1 and B7-DC in T cell-APC interactions, we examined the contribution of B7-H1 and B7-DC to CD4+ T cell activation by B cells, dendritic cells, and macrophages using anti-B7-H1, anti-B7-DC, and anti-PD-1 blocking mAbs. Anti-B7-H1 mAb and its Fab markedly inhibited the proliferation of anti-CD3-stimulated naive CD4+ T cells, but enhanced IL-2 and IFN-gamma production in the presence of macrophages. The inhibition of T cell proliferation by anti-B7-H1 mAb was abolished by neutralizing anti-IFN-gamma mAb. Coculture of CD4+ T cells and macrophages from IFN-gamma-deficient or wild-type mice showed that CD4+ T cell-derived IFN-gamma was mainly responsible for the inhibition of CD4+ T cell proliferation. Anti-B7-H1 mAb induced IFN-gamma-mediated production of NO by macrophages, and inducible NO synthase inhibitors abrogated the inhibition of CD4+ T cell proliferation by anti-B7-H1 mAb. These results indicated that the inhibition of T cell proliferation by anti-B7-H1 mAb was due to enhanced IFN-gamma production, which augmented NO production by macrophages, suggesting a critical role for B7-H1 on macrophages in regulating IFN-gamma production by naive CD4+ T cells and, hence, NO production by macrophages.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies, Blocking / pharmacology
  • B-Lymphocytes / immunology
  • B-Lymphocytes / metabolism
  • B7-1 Antigen / immunology
  • B7-1 Antigen / physiology
  • B7-H1 Antigen
  • CD4-Positive T-Lymphocytes / cytology
  • CD4-Positive T-Lymphocytes / drug effects
  • CD4-Positive T-Lymphocytes / immunology*
  • CD4-Positive T-Lymphocytes / metabolism
  • Cell Line
  • Cell Proliferation* / drug effects
  • Cricetinae
  • Dendritic Cells / immunology*
  • Dendritic Cells / metabolism*
  • Enzyme Inhibitors / pharmacology
  • Growth Inhibitors / deficiency
  • Growth Inhibitors / genetics
  • Growth Inhibitors / physiology
  • Interferon-gamma / deficiency
  • Interferon-gamma / genetics
  • Interferon-gamma / physiology*
  • Lymphocyte Activation / immunology
  • Macrophages, Peritoneal / immunology*
  • Macrophages, Peritoneal / metabolism
  • Male
  • Membrane Glycoproteins / antagonists & inhibitors*
  • Membrane Glycoproteins / immunology
  • Membrane Glycoproteins / physiology
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Nitric Oxide / biosynthesis*
  • Nitric Oxide / physiology
  • Nitric Oxide Synthase / antagonists & inhibitors
  • Nitric Oxide Synthase Type II
  • Ornithine / analogs & derivatives
  • Ornithine / pharmacology
  • Peptides / antagonists & inhibitors*
  • Peptides / immunology
  • Peptides / physiology
  • Programmed Cell Death 1 Ligand 2 Protein
  • Tryptophan Oxygenase / antagonists & inhibitors
  • omega-N-Methylarginine / pharmacology

Substances

  • Antibodies, Blocking
  • B7-1 Antigen
  • B7-H1 Antigen
  • Cd274 protein, mouse
  • Enzyme Inhibitors
  • Growth Inhibitors
  • Membrane Glycoproteins
  • Pdcd1lg2 protein, mouse
  • Peptides
  • Programmed Cell Death 1 Ligand 2 Protein
  • omega-N-Methylarginine
  • Nitric Oxide
  • N(G)-iminoethylornithine
  • Interferon-gamma
  • Ornithine
  • Tryptophan Oxygenase
  • Nitric Oxide Synthase
  • Nitric Oxide Synthase Type II
  • Nos2 protein, mouse