title: IL-27 limits central nervous system viral clearance by promoting IL-10 and enhances demyelination.
abstract: IL-27 is a pleiotropic member of the IL-6 and IL-12 cytokine family composed of the IL-27p28 and the EBV-induced gene 3. IL-27 and its receptor mRNA are both upregulated in the CNS during acute encephalomyelitis induced by the JHM strain of mouse hepatitis virus (JHMV) and sustained during viral persistence. Contributions of IL-27 to viral pathogenesis were evaluated by infection of IL-27Rα-chain-deficient (IL-27Rα(-/-)) mice. The absence of IL-27 signaling accelerated virus control within the CNS associated with increased IFN-γ secreting virus-specific CD4+ and CD8+ T cells. Abrogation of IL-27 signaling did not affect virus-specific CD8+ T cell-mediated IL-10 production or cytolytic activity or Foxp3+ regulatory T cell populations. However, IL-10 production by virus-specific CD4+ T cells was reduced significantly. Despite increased T cell-mediated antiviral function in IL-27Rα(-/-) mice, the virus persisted in the CNS at similar levels as in wild-type mice. Nevertheless, IL-27Rα(-/-) mice exhibited decreased clinical disease during persistence, coincident with less severe demyelination, the hallmark tissue damage associated with JHMV infection. Overall, these data demonstrate that in contrast to viral infections at other sites, IL-27 does not play a proinflammatory role during JHMV-induced encephalomyelitis. Rather, it limits CNS inflammation and impairs control of CNS virus replication via induction of IL-10 in virus-specific CD4+ T cells. Furthermore, in contrast to its protective role in limiting CNS autoimmunity and preventing immunopathology, these data define a detrimental role of IL-27 in promoting demyelination by delaying viral control.
authors.affiliation: Department of Neurosciences, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH 44195; and.
authors.forename: Maria Teresa P
authors.initials: MT
authors.lastname: de Aquino
authors.affiliation: Department of Neurosciences, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH 44195; and.
authors.forename: Parul
authors.initials: P
authors.lastname: Kapil
authors.affiliation: Department of Pathology, University of Southern California Keck School of Medicine, Los Angeles, CA 90089.
authors.forename: David R
authors.initials: DR
authors.lastname: Hinton
authors.affiliation: Department of Neurosciences, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH 44195; and.
authors.forename: Timothy W
authors.initials: TW
authors.lastname: Phares
authors.affiliation: Department of Neurosciences, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH 44195; and.
authors.forename: Shweta S
authors.initials: SS
authors.lastname: Puntambekar
authors.affiliation: Department of Neurosciences, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH 44195; and.
authors.forename: Carine
authors.initials: C
authors.lastname: Savarin
authors.affiliation: Department of Neurosciences, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH 44195; and.
authors.forename: Cornelia C
authors.initials: CC
authors.lastname: Bergmann
authors.affiliation: Department of Neurosciences, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH 44195; and stohlms2@ccf.org.
authors.forename: Stephen A
authors.initials: SA
authors.lastname: Stohlman
mesh_terms: D000818:Animals; D002490:Central Nervous System / Q000276:immunology* / Q000473:pathology; D018352:Coronavirus Infections / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D003711:Demyelinating Diseases; D004673:Encephalomyelitis, Acute Disseminated / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D016753:Interleukin-10 / Q000235:genetics / Q000276:immunology*; D007378:Interleukins / Q000235:genetics / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D006517:Murine hepatitis virus / Q000276:immunology*; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000473:pathology
chemical_list: C556062:IL10 protein, mouse; C486767:Il27 protein, mouse; D007378:Interleukins; D016753:Interleukin-10