Dendritic Cells in Multiple Sclerosis Lesions: Maturation Stage, Myelin Uptake, and Interaction With Proliferating T Cells

Serafini, Barbara; Rosicarelli, Barbara; Magliozzi, Roberta; Stigliano, Egidio; Capello, Elisabetta; Mancardi, Gianluigi; Aloisi, Francesca

doi:10.1093/jnen/65.2.124

Cited by 187 publications

(176 citation statements)

References 72 publications

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“…These professional APCs have been suggested to participate in restimulation of myelin-specific CD4 + T cells in the CNS (5,7,39,40). The identification of equal numbers of DCs in the CCR4 −/− and WT CNS at the onset of disease suggested no major differences in CNS migration, but cannot fully exclude that migratory deficits of CCR4 −/− DCs occur at a later time point during disease development.…”

Section: Discussionmentioning

confidence: 99%

CC chemokine receptor 4 is required for experimental autoimmune encephalomyelitis by regulating GM-CSF and IL-23 production in dendritic cells

Poppensieker

Otte

Schürmann

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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Dendritic cells (DCs) are pivotal for the development of experimental autoimmune encephalomyelitis (EAE). However, the mechanisms by which they control disease remain to be determined. This study demonstrates that expression of CC chemokine receptor 4 (CCR4) by DCs is required for EAE induction. CCR4 −/− mice presented enhanced resistance to EAE associated with a reduction in IL-23 and GM-CSF expression in the CNS. Restoring CCR4 on myeloid cells in bone marrow chimeras or intracerebral microinjection of CCR4-competent DCs, but not macrophages, restored EAE in CCR4 −/− mice, indicating that CCR4 + DCs are cellular mediators of EAE development. Mechanistically, CCR4 −/− DCs were less efficient in GM-CSF and IL-23 production and also T H -17 maintenance. Intraspinal IL-23 reconstitution restored EAE in CCR4 −/− mice, whereas intracerebral inoculation using IL-23 −/− DCs or GM-CSF −/− DCs failed to induce disease. Thus, CCR4-dependent GM-CSF production in DCs required for IL-23 release in these cells is a major component in the development of EAE. Our study identified a unique role for CCR4 in regulating DC function in EAE, harboring therapeutic potential for the treatment of CNS autoimmunity by targeting CCR4 on this specific cell type.chemokines | neuroinflammation M ultiple sclerosis (MS) is a chronic demyelinating disease of the human CNS (1). Experimental autoimmune encephalomyelitis (EAE), the animal model of MS, is mediated by myelin-specific CD4 + T cells activated by professional antigenpresenting cells (APCs) in peripheral lymphoid tissues (2, 3). In recent studies, both peripherally derived macrophages and DCs have been shown to present myelin antigens to invading autoreactive T cells in the CNS. This presentation initiates the recruitment of a second wave of leukocytes that damage the target organ via demyelination and axonal degeneration (4-8). Understanding the mechanisms responsible for the recruitment of APCs to the CNS and their local function is essential for the development of therapeutic strategies targeting the effector phase and thereby controlling disease progression.Chemokines and their G protein-coupled receptors are key regulators of leukocyte trafficking (9, 10). The CC chemokine receptor 4 (CCR4) is the cognate receptor for the CC chemokines CCL17 and CCL22, and is expressed on functionally distinct subsets of T cells, including activated T cells, T H 2 cells, and Treg cells. CCR4 has also been found on platelets, NK cells, macrophages, and DCs (11-15). DCs are important cellular sources for CCL17 and, in concert with macrophages, produce CCL22 during both homeostasis and inflammation (16,17). Different studies have suggested a critical role for CCR4 in the pathogenesis of EAE and MS. For example, elevated levels of the CCR4 ligands CCL17 or CCL22 have been found in the cerebrospinal fluid of MS patients (18-20). CCL22 protein has been identified in CNS-infiltrating leukocytes and microglia of EAE-induced mice, and CCR4 is expressed by invading leukocyte subsets (21,22). However, it rema...

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Section: Discussionmentioning

confidence: 99%

CC chemokine receptor 4 is required for experimental autoimmune encephalomyelitis by regulating GM-CSF and IL-23 production in dendritic cells

Poppensieker

Otte

Schürmann

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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“…Because DC-mediated aberrant T-cell activation has been correlated in previous studies with MS and autoimmune thyroid diseases [27,28], it is assumed that the development of small molecular weight CK2 inhibitors that inhibit specifically APRIL modification will be particularly useful in the therapy of autoimmune diseases. A recent report demonstrating that inhibition of CD83 prevented EAE in the murine animal model [24] supports this notion further.…”

Section: Discussionmentioning

confidence: 99%

“…Likewise, in rats, a positive therapeutic effect on experimental autoimmune myasthenia gravis has been reported by application of pentoxifylline, a drug that apparently interferes with CD83 expression [25,26]. Furthermore, CD83 1 DC were found to localize in inflamed lesions of patients who are afflicted with autoimmune thyroid diseases [27] or MS [28]. …”

mentioning

confidence: 95%

Phosphorylation of the HuR ligand APRIL by casein kinase 2 regulates CD83 expression

et al. 2009

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Fully mature DC and, to a lesser extent, activated T and B cells express CD83, a surface molecule that appears to fulfil an important role in efficient T-cell activation. Recently, it has been shown that CD83 mRNA is transported from the nucleus to the cytoplasm by an uncommon route, involving the cellular RNA-binding protein HuR and the nuclear export receptor CRM1. Moreover, the shuttle phosphoprotein APRIL (ANP32B) has been shown to be required for HuR-mediated nucleocytoplasmic translocation of the CD83 mRNA by acting as an adaptor that links HuR and CRM1. Here, we are able to report that casein kinase 2 (CK2) phosphorylates APRIL on residue threonine244 (Thr 244 ) and demonstrate that the CK2-specific inhibitor 4,5,6,7-tetrabromo-2-azabenzimidazole abolishes CD83 expression in activated Jurkat T cells by interfering with the nucleocytoplasmic translocation of CD83 mRNA. Depletion and knockdown studies demonstrate that the CK2 a 0 subunit is necessary for this regulation, whereas the CK2 a subunit seems to be dispensable. Taken together, the data presented significantly extend our knowledge of the complex regulation of CD83 mRNA processing and provides a novel strategy to interfere with CD83 expression.Key words: APRIL . Casein kinase 2 . CD83 . HuR . Leukocytes IntroductionMature DC are capable of sensitizing even naïve CD4 1 and CD8 1 T cells, and are therefore frequently termed ''nature's adjuvant''. Immature DC reside in the peripheral tissues and upon uptake of antigen and exposure to inflammatory stimuli, they migrate to the peripheral lymph nodes, where now fully matured, they induce antigen-specific T-cell response [1][2][3][4]. The DC maturation process includes the modulation of chemokine and chemokine receptors, as well as the up-regulation of several cytokines, costimulatory and adhesion molecules [5].Human CD83 serves as a major marker molecule for mature DC that belongs to the immunoglobulin super family [6,7]. This membrane-bound protein is also expressed, although to a significant lower extent, on activated T and B cells [7][8][9][10]. Moreover, a soluble form of CD83 is detectable at low levels in sera derived from healthy individuals, whereas in contrast, elevated levels are present in patients suffering from certain hematological malignancies [8,11]. Notwithstanding the fact that accumulating experimental evidence suggests that CD83 plays an important functional role in the regulation of DCmediated T-cell-specific immune response [12][13][14][15][16][17][18][19], the exact function of CD83 remains poorly understood [20][21][22]. Nevertheless, various disease-related findings suggest that CD83 holds great potential for future therapeutic application [23]. For example, EAE can be prevented in mice by applying a soluble form of CD83 [24]. Likewise, in rats, a positive therapeutic effect on experimental autoimmune myasthenia gravis has been reported by application of pentoxifylline, a drug that apparently interferes with CD83 expression [25,26]. Furthermore, CD83 1 DC were found to localize i...

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“…Il affecte cependant la transmigration des lymphocytes T CD4 et CD8, des monocytes et des cellules dendritiques myéloïdes et plasmacytoïdes circulantes [31]. Le FTY720 10 , un agoniste des récep-teurs du sphingosine-1 phosphate, qui inhibe de manière non spécifique la sortie des lymphocytes des ganglions lymphatiques et du thymus, a montré son efficacité au cours la SEP [32,39]. Ainsi, l'identification de molécules spécifiquement impliquées dans la migration des LT CD8 générateurs d'encéphalites permettrait de bloquer leur recrutement vers le système nerveux central, tout en respectant la migration des cellules nécessaires à l'immunosurveillance du SNC, limitant ainsi le risque de développer une infection opportuniste associée, par exemple, à une déplétion lymphocytaire T CD8 profonde.…”

Section: Resultsunclassified

“…Enfin, des interactions entre des cellules présentatrices d'antigène (CPA) et des LT CD8 proliférants sont détec-tées en périphérie de lésions de SEP [10]. La plupart des cellules résidentes du système nerveux central comme les astrocytes, les neurones et les oligodendrocytes expriment, au moins dans un contexte inflammatoire, des molécules du complexe majeur d'histocompatibilité de classe I (CMH-I), et peuvent donc, théoriquement, être la cible des LT CD8 [11].…”

Section: Synthèse Revuesunclassified

Migration et pathogénicité des lymphocytes T CD8 dans les maladies du système nerveux central

2015

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Dendritic Cells in Multiple Sclerosis Lesions: Maturation Stage, Myelin Uptake, and Interaction With Proliferating T Cells

Cited by 187 publications

References 72 publications

CC chemokine receptor 4 is required for experimental autoimmune encephalomyelitis by regulating GM-CSF and IL-23 production in dendritic cells

CC chemokine receptor 4 is required for experimental autoimmune encephalomyelitis by regulating GM-CSF and IL-23 production in dendritic cells

Phosphorylation of the HuR ligand APRIL by casein kinase 2 regulates CD83 expression

Migration et pathogénicité des lymphocytes T CD8 dans les maladies du système nerveux central

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