EAE, an animal model for MS, is a Th17 and Th1-cell-mediated autoimmune disease, but the mechanisms leading to priming of encephalitogenic T cells in autoimmune neuroinflammation are poorly understood. To investigate the role of plasmacytoid DC (pDC) in the initiation of autoimmune Th17-and Th1-cell responses and EAE, we depleted pDC with anti-pDC Ag-1 (anti-PDCA1) mAb prior to immunization of C57BL/6 mice with myelin oligodendrocyte glycoprotein (MOG). pDC-depleted mice developed less severe clinical and histopathological signs of EAE than control mice, which demonstrates a promoting role for pDC in the initiation of EAE. The levels of type I IFN were much lower in the sera from anti-PDCA1-treated mice. However, neutralization of type I IFN ameliorated the early phase of EAE but did not alter the severity of disease. Thus, only a minor part of the EAE-promoting effect of pDC appears to be mediated by IFN-a/b secretion. The numbers of MOG-specific Th17 cells, but not Th1 cells, were lower in spleen from anti-PDCA1-treated mice compared with controls. In contrast, pDC depletion a week after MOG immunization resulted in more severe clinical signs of EAE.In conclusion, we demonstrate that pDC promote initiation of MOG-induced Th17-cell responses and EAE.Key words: Autoimmunity . DC . EAE/MS . T cells . Type I IFN
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IntroductionEAE is an animal model for the human autoimmune demyelinating disease MS [1]. The pathological changes in the CNS during EAE are very similar to MS with perivascular infiltrates of T cells, B cells and macrophages [2]. Murine EAE is induced by injection of myelin autoantigens such as myelin oligodendrocyte glycoprotein (MOG) in CFA containing killed Mycobacterium tuberculosis and pertussis toxin. EAE was previously thought to be a purely IL-12-driven Th1-mediated autoimmune disease [3].However Langrish et al. demonstrated that proinflammatory IL-17-producing Th17 cells mediate EAE [4]. Murine-naïve CD4
CD251 6]. Recently it wasshown that different epitopes of MOG predominately induce a Th1 or Th17 response, which influences the lesion distribution and clinical symptoms of EAE and suggests a promoting role for both Th17 and Th1 cells in MOG-induced EAE [7]. DC are key actors when an adaptive immune response is initiated [8]. There are two major DC subsets in mice, which are characterized by differential expression of cell surface markers [9] . pDC also have a powerful ability to modify the adaptive immune response, e.g. T-cell differentiation [11,12]. The expression of costimulatory molecules differs between mDC and pDC, e.g. maturation leads to upregulation of B7 molecules on mDC, but downregulation of these molecules on pDC [13,14]. Moreover, mDC and pDC differ in their expression of TLR and response to TLR ligation. TLR7 and TLR9 ligation results in type I IFN production in pDC because of constitutive expression of IFN regulatory factor-7, whereas ligation of these receptors leads to IL-12 production in mDC [15,16]. We have previously shown that TLR9 a...