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

Timothy W. Phares, Chandran Ramakrishna, Gabriel I. Parra, Alan Epstein, Lieping Chen, Roscoe Atkinson, Stephen A. Stohlman, Cornelia C. Bergmann

Research output: Contribution to journalArticle

Abstract

The neurotropic coronavirus JHM strain of mouse hepatitis virus persists in oligodendroglia despite the presence of virusspecific 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-γ or IFN-α/β receptor demonstrated that B7-H1 expression on oligodendroglia is predominantly regulated by IFN-γ. Ab blockade of B7-H1 on oligodendroglia in vitro enhanced IFN-γ 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.

Original languageEnglish (US)
Pages (from-to)5430-5438
Number of pages9
JournalJournal of Immunology
Volume182
Issue number9
DOIs
StatePublished - May 1 2009

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ASJC Scopus subject areas

  • Immunology
  • Medicine(all)

Cite this

Phares, T. W., Ramakrishna, C., Parra, G. I., Epstein, A., Chen, L., Atkinson, R., Stohlman, S. A., & Bergmann, C. C. (2009). Target-dependent B7-H1 regulation contributes to clearance of central nervous sysyem infection and dampens morbidity. Journal of Immunology, 182(9), 5430-5438. https://doi.org/10.4049/jimmunol.0803557