TY - JOUR
T1 - Target-dependent B7-H1 regulation contributes to clearance of central nervous sysyem infection and dampens morbidity
AU - Phares, Timothy W.
AU - Ramakrishna, Chandran
AU - Parra, Gabriel I.
AU - Epstein, Alan
AU - Chen, Lieping
AU - Atkinson, Roscoe
AU - Stohlman, Stephen A.
AU - Bergmann, Cornelia C.
PY - 2009/5/1
Y1 - 2009/5/1
N2 - 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.
AB - 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.
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U2 - 10.4049/jimmunol.0803557
DO - 10.4049/jimmunol.0803557
M3 - Article
C2 - 19380790
AN - SCOPUS:66949159493
SN - 0022-1767
VL - 182
SP - 5430
EP - 5438
JO - Journal of Immunology
JF - Journal of Immunology
IS - 9
ER -