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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.