Abstract
BackgroundAutoreactive Th1 and Th17 cells are believed to mediate the pathology of multiple sclerosis in the central nervous system (CNS). Their interaction with microglia and astrocytes in the CNS is crucial for the regulation of the neuroinflammation. Previously, we have shown that only Th1 but not Th17 effectors activate microglia. However, it is not clear which cells are targets of Th17 effectors in the CNS.MethodsTo understand the effects driven by Th17 cells in the CNS, we induced experimental autoimmune encephalomyelitis in wild-type mice and CD4+ T cell-specific integrin α4-deficient mice where trafficking of Th1 cells into the CNS was affected. We compared microglial and astrocyte response in the brain and spinal cord of these mice. We further treated astrocytes with supernatants from highly pure Th1 and Th17 cultures and assessed the messenger RNA expression of neurotrophic factors, cytokines and chemokines, using real-time PCR. Data obtained was analyzed using the Kruskal-Wallis test.ResultsWe observed in α4-deficient mice weak microglial activation but comparable astrogliosis to that of wild-type mice in the regions of the brain populated with Th17 infiltrates, suggesting that Th17 cells target astrocytes and not microglia. In vitro, in response to supernatants from Th1 and Th17 cultures, astrocytes showed altered expression of neurotrophic factors, pro-inflammatory cytokines and chemokines. Furthermore, increased expression of chemokines in Th1- and Th17-treated astrocytes enhanced recruitment of microglia and transendothelial migration of Th17 cells in vitro.ConclusionOur results demonstrate the delicate interaction between T cell subsets and glial cells and how they communicate to mediate their effects. Effectors of Th1 act on both microglia and astrocytes whereas Th17 effectors preferentially target astrocytes to promote neuroinflammation.
Highlights
Autoreactive Th1 and Th17 cells are believed to mediate the pathology of multiple sclerosis in the central nervous system (CNS)
Blockade of Th1 infiltration into the CNS during EAE impairs astrogliosis in the spinal cord but not in the brain Previously, we have demonstrated that only effector molecules secreted by Th1 cells but not Th17 cells activate microglia [13]
We have previously shown that only Th1-derived effectors influenced the phenotype and function of microglia whereas Th17 cells had no direct effects [13]
Summary
Autoreactive Th1 and Th17 cells are believed to mediate the pathology of multiple sclerosis in the central nervous system (CNS) Their interaction with microglia and astrocytes in the CNS is crucial for the regulation of the neuroinflammation. Infiltrating effector T cells are in constant crosstalk with resident glial cells, and recently, we have demonstrated that effector molecules secreted by Th1 cells but not Th17 cells influence the phenotype and function of microglia [13]. This was rather puzzling, considering the fact that Th17 cells are highly pathogenic and microglia are highly immunoreactive cell types in the CNS. We identified astrocytes as targets of Th17 cells in the CNS and studied the ability of effector molecules released by Th1 and Th17 cells to influence their phenotype and function
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