TY - JOUR
T1 - Interleukin 10 modulation of pathogenic Th17 cells during fatal alphavirus encephalomyelitis
AU - Kulcsar, Kirsten A.
AU - Baxter, Victoria K.
AU - Greene, Ivorlyne P.
AU - Griffin, Diane E.
PY - 2014/11/11
Y1 - 2014/11/11
N2 - 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.
AB - 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.
KW - GM-CSF
KW - Immunopathology
KW - Interleukin-10
KW - Sindbis virus
KW - Viral encephalitis
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UR - http://www.scopus.com/inward/citedby.url?scp=84909609626&partnerID=8YFLogxK
U2 - 10.1073/pnas.1418966111
DO - 10.1073/pnas.1418966111
M3 - Article
C2 - 25362048
AN - SCOPUS:84909609626
VL - 111
SP - 16053
EP - 16058
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
SN - 0027-8424
IS - 45
ER -