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Interleukin 10 modulation of pathogenic Th17 cells during fatal alphavirus encephalomyelitis
- Kulcsar, Kirsten A., Baxter, Victoria K., Greene, Ivorlyne P., Griffin, Diane E.
- Proceedings of the National Academy of Sciences of the United States of America 2014 v.111 no.45 pp. 16053-16058
- central nervous system, disease course, encephalitis, immune response, interleukin-10, pathogenesis, phenotype, viruses
- 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.