The mean clinicalEAEscore was only mildly reduced inDC-depleted mice when DCs were ablated beforeEAEinduction. The frequency of activatedTh cells was not altered, andMOG-inducedTh17 orTh1-cell responses were not altered, in the spleens ofDC-depleted mice. Similar results were obtained ifDCswere ablated the first 10 days afterMOGimmunization with repeatedDCdepletions.

Unexpectedly, transient depletion of DCs did not affect priming or differentiation of MOG-inducedTh17 andTh1-cell Pexidartinib price responses or the incidence ofEAE. Thus, the mechansim of priming ofTh cells inEAEremains to be elucidated. Dendritic cells (DCs) are key actors of adaptive immune responses against infections [1-3]. There are several DC subsets in mice which are characterized by differential expression of cell surface markers and their location;

e.g. myeloid DCs (mDCs), plasmacytoid DCs (pDCs), dermal DCs, CD11b+ DCs, and CD11b− DCs [4, 5]. Ly6Chi monocytes are considered to be precursors of inflammatory DCs (inflDCs) which are recruited to site of inflammation [4]. InflDCs express intermediate to high levels of CD11c and MHC class II (MHC II). mDCs are highly specialized in priming naïve T cells in vitro GSK-3 inhibition [3]. In vivo depletion of murine CD11c+ mDCs by diphtheria toxin (DTx)-based transgenic systems has demonstrated an indispensible role for DCs during priming of CD8+ T-cell responses to viruses, intracellular bacteria and malaria parasites [1, 6]. Priming of Th1 responses and Th2 responses to parasites also depends on DCs [2, 7]. Furthermore, ablation of DCs leads to dissemination CYTH4 of Streptococcus pyogenes [8]. In contrast, constitutive ablation of CD11c+ DCs leads to spontaneous fatal autoimmunity, high numbers of Th17 and Th1 cells and production of autoantibodies such as antinuclear Ab [9]. This suggests that DC-mediated deletion of autoreactive single-positive thymocytes is important and failure leads to the observed pathology [9]. Constitutive

deletion of DCs in vivo in lupus-prone mice results in amelioration of disease, but DCs are not required for initial priming of autoimmune Th cells. Instead, DCs are important for functional differentiation and expansion of T cells [10]. Little is known about the role of mDCs in priming and de novo differentiation of autoimmune Th cells in the organ-specific autoimmune disease EAE, an animal model for human multiple sclerosis [11]. We have previously demonstrated that myelin oligodendrocyte glycoprotein (MOG)-induced EAE is mediated by MyD88-dependent mechanisms [12]. IL-6 expression by mDCs depended on MyD88 and was upregulated between 4 and 10 days after MOG immunization [12]. Furthermore, depletion of pDC prior to MOG immunization ameliorated the clinical and histopathological signs of MOG-induced EAE compared with control mice [13].