Target-dependent B7-H1 regulation contributes to clearance of central nervous system infection and dampens morbidity

J Immunol. 2009 May 1;182(9):5430-8. doi: 10.4049/jimmunol.0803557.

Abstract

The neurotropic coronavirus JHM strain of mouse hepatitis virus persists in oligodendroglia despite the presence of virus-specific CD8 T cells. Expression of programmed death 1 (PD-1) and B7-H1 were studied during acute and persistent infection to examine whether this negative regulatory mechanism contributes to CNS viral persistence. The majority of CNS-infiltrating CD8 T cells expressed PD-1, with the highest levels on virus-specific CD8 T cells. Moreover, despite control of infectious virus, CD8 T cells within the CNS of persistently infected mice maintained high PD-1 expression. Analysis of virus-susceptible target cells in vivo revealed that B7-H1 expression was regulated in a cell type-dependent manner. Oligodendroglia and microglia up-regulated B7-H1 following infection; however, although B7-H1 expression on oligodendroglia was prominent and sustained, it was significantly reduced and transient on microglia. Infection of mice deficient in the IFN-gamma or IFN-alpha/beta receptor demonstrated that B7-H1 expression on oligodendroglia is predominantly regulated by IFN-gamma. Ab blockade of B7-H1 on oligodendroglia in vitro enhanced IFN-gamma secretion by virus-specific CD8 T cells. More efficient virus control within the CNS of B7-H1-deficient mice confirmed inhibition of CD8 T cell function in vivo. Nevertheless, the absence of B7-H1 significantly increased morbidity without altering demyelination. These data are the first to demonstrate glia cell type-dependent B7-H1 regulation in vivo, resulting in adverse effects on antiviral CD8 T cell function. However, the beneficial role of PD-1:B7-H1 interactions in limiting morbidity highlights the need to evaluate tissue-specific intervention strategies.

Publication types

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

MeSH terms

  • Animals
  • Antigens, Surface / biosynthesis
  • Antigens, Surface / genetics
  • Antigens, Surface / physiology*
  • Apoptosis Regulatory Proteins / biosynthesis
  • Apoptosis Regulatory Proteins / genetics
  • Apoptosis Regulatory Proteins / physiology*
  • B7-1 Antigen / genetics
  • B7-1 Antigen / physiology*
  • B7-H1 Antigen
  • CD8-Positive T-Lymphocytes / immunology
  • CD8-Positive T-Lymphocytes / pathology
  • CD8-Positive T-Lymphocytes / virology
  • Cell Line
  • Cell Movement / immunology
  • Coronavirus Infections / immunology
  • Coronavirus Infections / mortality*
  • Coronavirus Infections / pathology
  • Coronavirus Infections / prevention & control*
  • Membrane Glycoproteins / antagonists & inhibitors
  • Membrane Glycoproteins / deficiency
  • Membrane Glycoproteins / genetics
  • Membrane Glycoproteins / physiology*
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Transgenic
  • Murine hepatitis virus / immunology
  • Neuroglia / immunology
  • Neuroglia / pathology
  • Neuroglia / virology
  • Peptides / antagonists & inhibitors
  • Peptides / deficiency
  • Peptides / genetics
  • Peptides / physiology*
  • Programmed Cell Death 1 Receptor
  • Spinal Cord Diseases / immunology
  • Spinal Cord Diseases / mortality*
  • Spinal Cord Diseases / pathology
  • Spinal Cord Diseases / prevention & control*
  • Virus Replication / immunology

Substances

  • Antigens, Surface
  • Apoptosis Regulatory Proteins
  • B7-1 Antigen
  • B7-H1 Antigen
  • Cd274 protein, mouse
  • Membrane Glycoproteins
  • Pdcd1 protein, mouse
  • Peptides
  • Programmed Cell Death 1 Receptor