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          Institute: MPI für Neurobiologie     Collection: Neuroimmunology     Display Documents

ID: 479816.0, MPI für Neurobiologie / Neuroimmunology
Nicotinic acid adenine dinucleotide phosphate-mediated calcium signalling in effector T cells regulates autoimmunity of the central nervous system
Authors:Cordiglieri, C.; Odoardi, F.; Zhang, B.; Nebel, M.; Kawakami, N.; Klinkert, W. E. F.; Lodygin, D.; Luhder, F.; Breunig, E.; Schild, D.; Ulaganathan, V. K.; Dornmair, K.; Dammermann, W.; Potter, B. V. L.; Guse, A. H.; Flügel, A.
Date of Publication (YYYY-MM-DD):2010-07
Title of Journal:Brain
Journal Abbrev.:Brain
Start Page:1930
End Page:1943
Review Status:Peer-review
Audience:Not Specified
Abstract / Description:Nicotinic acid adenine dinucleotide phosphate represents a newly identified second messenger in T cells involved in antigen receptor-mediated calcium signalling. Its function in vivo is, however, unknown due to the lack of biocompatible inhibitors. Using a recently developed inhibitor, we explored the role of nicotinic acid adenine dinucleotide phosphate in autoreactive effector T cells during experimental autoimmune encephalomyelitis, the animal model for multiple sclerosis. We provide in vitro and in vivo evidence that calcium signalling controlled by nicotinic acid adenine dinucleotide phosphate is relevant for the pathogenic potential of autoimmune effector T cells. Live two photon imaging and molecular analyses revealed that nicotinic acid adenine dinucleotide phosphate signalling regulates T cell motility and re-activation upon arrival in the nervous tissues. Treatment with the nicotinic acid adenine dinucleotide phosphate inhibitor significantly reduced both the number of stable arrests of effector T cells and their invasive capacity. The levels of pro-inflammatory cytokines interferon-gamma and interleukin-17 were strongly diminished. Consecutively, the clinical symptoms of experimental autoimmune encephalomyelitis were ameliorated. In vitro, antigen-triggered T cell proliferation and cytokine production were evenly suppressed. These inhibitory effects were reversible: after wash-out of the nicotinic acid adenine dinucleotide phosphate antagonist, the effector T cells fully regained their functions. The nicotinic acid derivative BZ194 induced this transient state of non-responsiveness specifically in post-activated effector T cells. Naive and long-lived memory T cells, which express lower levels of the putative nicotinic acid adenine dinucleotide phosphate receptor, type 1 ryanodine receptor, were not targeted. T cell priming and recall responses in vivo were not reduced. These data indicate that the nicotinic acid adenine dinucleotide phosphate/calcium signalling pathway is essential for the recruitment and the activation of autoaggressive effector T cells within their target organ. Interference with this signalling pathway suppresses the formation of autoimmune inflammatory lesions and thus might qualify as a novel strategy for the treatment of T cell mediated autoimmune diseases.
Free Keywords:experimental autoimmune encephalomyelitis; multiple sclerosis; T cell signalling; nicotinic acid adenine dinucleotide phosphate; intravital imaging
External Publication Status:published
Document Type:Article
Version Comment:Automatic journal name synchronization
Affiliations:MPI für Neurobiologie/Neuroimmunology (Wekerle)
External Affiliations:[Odoardi, Francesca; Lodygin, Dimtri; Luehder, Fred; Fluegel, Alexander] Univ Gottingen, Dept Neuroimmunol, Inst Multiple Sclerosis Res, D-37073 Gottingen, Germany.; [Odoardi, Francesca; Fluegel, Alexander] Univ Munich, Inst Immunol, D-80336 Munich, Germany.; [Zhang, Bo; Potter, Barry V. L.] Univ Bath, Dept Pharm & Pharmacol, Wolfson Lab Med Chem, Bath BA2 7AY, Avon, England.; [Nebel, Merle; Dammermann, Werner; Guse, Andreas H.] Univ Med Ctr Hamburg Eppendorf, Ctr Med Expt, Calcium Signalling Grp, Inst Biochem & Mol Biol 1, D-20246 Hamburg, Germany.; [Breunig, Esther; Schild, Detlev] Univ Gottingen, Dept Neurophysiol & Cellular Biophys, D-37083 Gottingen, Germany.; [Dornmair, Klaus] Univ Munich, Inst Clin Neuroimmunol, D-81377 Munich, Germany.; [Odoardi, Francesca; Lodygin, Dimtri; Luehder, Fred; Fluegel, Alexander] Hertie Fdn, D-37073 Gottingen, Germany.
Identifiers:ISI:000279473900008 [ID No:1]
ISSN:0006-8950 [ID No:2]
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