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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(+)IFN?(+) 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.

SUBMITTER: Kulcsar KA

PROVIDER: S-EPMC4234572 | biostudies-literature | 2014 Nov

REPOSITORIES: biostudies-literature

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Interleukin 10 modulation of pathogenic Th17 cells during fatal alphavirus encephalomyelitis.

Kulcsar Kirsten A KA Baxter Victoria K VK Greene Ivorlyne P IP Griffin Diane E DE

Proceedings of the National Academy of Sciences of the United States of America 20141031 45

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 ...[more]

PMID: 25362048

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Project description:BackgroundThere is consensus that experimental autoimmune encephalomyelitis (EAE) can be mediated by myelin specific T cells of Th1 as well as of Th17 phenotype, but the contribution of either subset to the pathogenic process has remained controversial. In this report, we compare functional differences and pathogenic potential of "monoclonal" T cell lines that recognize myelin oligodendrocyte glycoprotein (MOG) with the same transgenic TCR but are distinguished by an IFN-? producing Th1-like and IL-17 producing Th17-like cytokine signature.Methods and findingsCD4+ T cell lines were derived from the transgenic mouse strain 2D2, which expresses a TCR recognizing MOG peptide 35-55 in the context of I-A(b). Adoptive transfer of Th1 cells into lymphopenic (Rag2?/?) recipients, predominantly induced "classic" paralytic EAE, whereas Th17 cells mediated "atypical" ataxic EAE in approximately 50% of the recipient animals. Combination of Th1 and Th17 cells potentiated the encephalitogenicity inducing classical EAE exclusively. Th1 and Th17 mediated EAE lesions differed in their composition but not in their localization within the CNS. While Th1 lesions contained IFN-?, but no IL-17 producing T cells, the T cells in Th17 lesions showed plasticity, substantially converting to IFN-? producing Th1-like cells. Th1 and Th17 cells differed drastically by their lytic potential. Th1 but not Th17 cells lysed autoantigen presenting astrocytes and fibroblasts in vitro in a contact-dependent manner. In contrast, Th17 cells acquired cytotoxic potential only after antigenic stimulation and conversion to IFN-? producing Th1 phenotype.ConclusionsOur data demonstrate that both Th1 and Th17 lineages possess the ability to induce CNS autoimmunity but can function with complementary as well as differential pathogenic mechanisms. We propose that Th17-like cells producing IL-17 are required for the generation of atypical EAE whereas IFN-? producing Th1 cells induce classical EAE.

Dataset Information

Interleukin 10 modulation of pathogenic Th17 cells during fatal alphavirus encephalomyelitis.

Publications

Interleukin 10 modulation of pathogenic Th17 cells during fatal alphavirus encephalomyelitis.

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