title: Interleukin 10 modulation of pathogenic Th17 cells during fatal alphavirus encephalomyelitis.
abstract: Mosquito-borne alphaviruses are important causes of epidemic encephalomyelitis. Neuronal cell death during fatal alphavirus encephalomyelitis is immune-mediated; however, the types of cells involved and their regulation have not been determined. We show that the virus-induced inflammatory response was accompanied by production of the regulatory cytokine IL-10, and in the absence of IL-10, paralytic disease occurred earlier and mice died faster. To determine the reason for accelerated disease in the absence of IL-10, immune responses in the CNS of IL-10(-/-) and wild-type (WT) mice were compared. There were no differences in the amounts of brain inflammation or peak virus replication; however, IL-10(-/-) animals had accelerated and increased infiltration of CD4(+)IL-17A(+) and CD4(+)IL-17A(+)IFNγ(+) cells compared with WT animals. Th17 cells infiltrating the brain demonstrated a pathogenic phenotype with the expression of the transcription factor, Tbet, and the production of granzyme B, IL-22, and GM-CSF, with greater production of GM-CSF in IL-10(-/-) mice. Therefore, in fatal alphavirus encephalomyelitis, pathogenic Th17 cells enter the CNS at the onset of neurologic disease and, in the absence of IL-10, appear earlier, develop into Th1/Th17 cells more often, and have greater production of GM-CSF. This study demonstrates a role for pathogenic Th17 cells in fatal viral encephalitis.
authors.affiliation: Program in Cellular and Molecular Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205; and W. Harry Feinstone Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205.
authors.forename: Kirsten A
authors.initials: KA
authors.lastname: Kulcsar
authors.affiliation: Program in Cellular and Molecular Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205; and W. Harry Feinstone Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205.
authors.forename: Victoria K
authors.initials: VK
authors.lastname: Baxter
authors.affiliation: Program in Cellular and Molecular Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205; and W. Harry Feinstone Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205.
authors.forename: Ivorlyne P
authors.initials: IP
authors.lastname: Greene
authors.affiliation: Program in Cellular and Molecular Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205; and W. Harry Feinstone Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205 dgriffi6@jhu.edu.
authors.forename: Diane E
authors.initials: DE
authors.lastname: Griffin
mesh_terms: D018354:Alphavirus Infections / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D000818:Animals; D001921:Brain / Q000276:immunology / Q000473:pathology / Q000821:virology; D004679:Encephalomyelitis / Q000235:genetics / Q000276:immunology* / Q000473:pathology / Q000821:virology; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000235:genetics / Q000276:immunology; D053804:Granzymes / Q000235:genetics / Q000276:immunology; D007371:Interferon-gamma / Q000235:genetics / Q000276:immunology; D016753:Interleukin-10 / Q000235:genetics / Q000276:immunology*; D007378:Interleukins / Q000235:genetics / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D012845:Sindbis Virus / Q000276:immunology*; D018417:Th1 Cells / Q000276:immunology / Q000473:pathology; D058504:Th17 Cells / Q000276:immunology* / Q000473:pathology; D000097043:Interleukin-22
chemical_list: D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D053804:Granzymes; D007371:Interferon-gamma; D016753:Interleukin-10; D007378:Interleukins; D000097043:Interleukin-22; C556062:IL10 protein, mouse; C509214:Gzmb protein, mouse
keywords: GM-CSF; Sindbis virus; immunopathology; interleukin-10; viral encephalitis