title: Target-dependent B7-H1 regulation contributes to clearance of central nervous system infection and dampens morbidity.
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.
authors.affiliation: Department of Neurosciences, Lerner Research Institute, The Cleveland Clinic, Cleveland, OH 44195, USA.
authors.forename: Timothy W
authors.initials: TW
authors.lastname: Phares
authors.forename: Chandran
authors.initials: C
authors.lastname: Ramakrishna
authors.forename: Gabriel I
authors.initials: GI
authors.lastname: Parra
authors.forename: Alan
authors.initials: A
authors.lastname: Epstein
authors.forename: Lieping
authors.initials: L
authors.lastname: Chen
authors.forename: Roscoe
authors.initials: R
authors.lastname: Atkinson
authors.forename: Stephen A
authors.initials: SA
authors.lastname: Stohlman
authors.forename: Cornelia C
authors.initials: CC
authors.lastname: Bergmann
mesh_terms: D000818:Animals; D000954:Antigens, Surface / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D051017:Apoptosis Regulatory Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D018122:B7-1 Antigen / Q000235:genetics / Q000502:physiology*; D060890:B7-H1 Antigen; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000473:pathology / Q000821:virology; D002460:Cell Line; D002465:Cell Movement / Q000276:immunology; D018352:Coronavirus Infections / Q000276:immunology / Q000401:mortality* / Q000473:pathology / Q000517:prevention & control*; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D006517:Murine hepatitis virus / Q000276:immunology; D009457:Neuroglia / Q000276:immunology / Q000473:pathology / Q000821:virology; D010455:Peptides / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D061026:Programmed Cell Death 1 Receptor; D013118:Spinal Cord Diseases / Q000276:immunology / Q000401:mortality* / Q000473:pathology / Q000517:prevention & control*; D014779:Virus Replication / Q000276:immunology
chemical_list: D000954:Antigens, Surface; D051017:Apoptosis Regulatory Proteins; D018122:B7-1 Antigen; D060890:B7-H1 Antigen; C498919:Cd274 protein, mouse; D008562:Membrane Glycoproteins; C491383:Pdcd1 protein, mouse; D010455:Peptides; D061026:Programmed Cell Death 1 Receptor