Cutting Edge: Central Nervous System Plasmacytoid Dendritic Cells Regulate the Severity of Relapsing Experimental Autoimmune Encephalomyelitis

Bailey-Bucktrout, Samantha L.; Caulkins, Sarah C.; Goings, Gwendolyn E.; Fischer, Jens A. A.; Dzionek, Andrzej; Miller, Stephen D.

doi:10.4049/jimmunol.180.10.6457

Cited by 130 publications

(138 citation statements)

References 27 publications

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“…1). Previous studies, using severalfold higher doses of anti-PDCA1 mAb, have demonstrated that pDC numbers are normalized 3-5 days following anti-PDCA1 treatment [18,20]. The incidence of EAE was 62% and the maximum mean EAE score of 1.270.4 (po0.05) for anti-PDCA1-treated mice, compared with 92% incidence and a maximum mean EAE score of 2.870.5 for normal IgG-treated mice ( Fig.…”

Section: Results Pdc Promote Eaementioning

confidence: 92%

“…Thus, we could not observe any influence of pDC on ICOS signaling in T cells in our system. In a recent study, the clinical signs of EAE exacerbated considerably if pDC were depleted during the peak of the disease process [18]. To reproduce the results of this study in MOGimmunized C57BL/6 mice, we depleted pDC 8 days after immunization and then every other day for a total of four treatments (Fig.…”

Section: Icos Signaling In T Cells Is Not Affected By the Pdc Depletionmentioning

confidence: 99%

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Plasmacytoid DC promote priming of autoimmune Th17 cells and EAE

et al. 2009

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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 Supporting Information available online 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...

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Section: Results Pdc Promote Eaementioning

confidence: 92%

Section: Icos Signaling In T Cells Is Not Affected By the Pdc Depletionmentioning

confidence: 99%

Plasmacytoid DC promote priming of autoimmune Th17 cells and EAE

et al. 2009

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“…In experimental autoimmune encephalomyelitis, an animal model of human MS, a critical tolerogenic effect of pDCs was demonstrated (14). Unlike myeloid DCs, pDCs had only a minor role in T cell activation and epitope spreading, but negatively regulated pathogenic CNS CD4 + T cell responses, suggesting a regulatory role during experimental neuroinflammation (14). However, it has to be noted critically that the exact mechanism of pDC accumulation and their role during CNS inflammation are not well understood.…”

mentioning

confidence: 99%

“…Active recruitment of pDCs into the CNS and their accumulation in white matter lesions and leptomeninges of MS brains has also been demonstrated (13). In experimental autoimmune encephalomyelitis, an animal model of human MS, a critical tolerogenic effect of pDCs was demonstrated (14). Unlike myeloid DCs, pDCs had only a minor role in T cell activation and epitope spreading, but negatively regulated pathogenic CNS CD4 + T cell responses, suggesting a regulatory role during experimental neuroinflammation (14).…”

mentioning

confidence: 99%

An Imbalance of Two Functionally and Phenotypically Different Subsets of Plasmacytoid Dendritic Cells Characterizes the Dysfunctional Immune Regulation in Multiple Sclerosis

Schwab¹,

Zozulya²,

Kieseier

et al. 2010

The Journal of Immunology

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“…pDCs were found to limit the differentiation of effector Th1 and Th17 cells in the EAE model in an indoleamine 2,3-dioxygenase (IDO)-dependent manner; these effects are not associated with the differentiation of FoxP3 þ Tregs. 55 Taken together, these data show that, both in the periphery and the CNS, DCs control the balance between effector and regulatory T cells and consequently the development of autoimmune disorders.…”

Section: Role Of Dcs In the Peripheral Activation Of T Cellsmentioning

confidence: 80%

Role and therapeutic value of dendritic cells in central nervous system autoimmunity

2014

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Dendritic cells (DCs) are professional antigen-presenting cells that control the generation of adaptive immunity. Consequently, DCs have a central role in the induction of protective immunity to pathogens and also in the pathogenic immune response responsible for the development and progression of autoimmune disorders. Thus the study of the molecular pathways that control DC development and function is likely to result in new strategies for the therapeutic manipulation of the immune response. In this review, we discuss the role and therapeutic value of DCs in autoimmune diseases, with a special focus on multiple sclerosis. Cell Death and Differentiation (2015) 22, 215-224; doi:10.1038/cdd.2014; published online 29 August 2014 FactsDendritic cells (DCs) control central and peripheral tolerance through their effects on effector and regulatory T cells. Specific signaling pathways regulate the ability of different DC populations to promote effector and regulatory T-cell responses. Abnormalities in DC numbers, recruitment and function contribute to the pathology of multiple sclerosis (MS) and can be partially overcome by the use of disease-modifying therapies and the targeting of specific molecular pathways. Nanotechnology provides new tools for the modulation of DC activity in vivo and the therapeutic induction of antigenspecific tolerance in immune-mediated disorders. Open QuestionsAlthough DC populations that promote the development of forkhead box P3-positive (FoxP3 þ ) regulatory T cells (Tregs) have been identified, it is not yet clear whether these populations constitute separate tolerogenic DC lineages or represent alternative activation or maturation states of other DC populations. What are the different molecular pathways that control the DC's ability to prime effector or tolerogenic T-cell responses?There is an unmet clinical need for the development of methods for the efficient and consistent generation of tolerogenic DCs in vitro and in vivo that can be implemented in large-scale clinical setups.Dendritic cells (DCs) are professional antigen-presenting cells (APCs) that control the activation and polarization of T cells into specific lineages and, consequently, the generation of antigen-specific antibody and T-cell responses. 1 In the context of an infectious challenge, the induction of pathogenspecific immune responses provides protective immunity to fight the infection. However, in the context of autoimmune diseases DCs regulate the balance between pathogenic and regulatory immune mechanisms, controlling disease onset and progression. Thus, DCs have a central role in the control of the adaptive immune response to pathogens and selftissues and therefore constitute potential targets for the therapeutic modulation of the immune response. In this review, we discus the role of DCs in autoimmune diseases, with a special emphasis on their role in the modulation of central nervous system (CNS) inflammation in MS. Received 12.6.14; accepted 23.6.14; Edited by H-U Simon; published online 29.8.14 Abbreviations: A...

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Cutting Edge: Central Nervous System Plasmacytoid Dendritic Cells Regulate the Severity of Relapsing Experimental Autoimmune Encephalomyelitis

Cited by 130 publications

References 27 publications

Plasmacytoid DC promote priming of autoimmune Th17 cells and EAE

Plasmacytoid DC promote priming of autoimmune Th17 cells and EAE

An Imbalance of Two Functionally and Phenotypically Different Subsets of Plasmacytoid Dendritic Cells Characterizes the Dysfunctional Immune Regulation in Multiple Sclerosis

Role and therapeutic value of dendritic cells in central nervous system autoimmunity

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