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. and Flugel, A., 2010. Nicotinic acid adenine dinucleotide phosphate-mediated calcium signalling in effector T cells regulates autoimmunity of the central nervous system. Brain, 133 (7), pp. 1930-1943.
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.
|Item Type ||Articles|
|Creators||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. and Flugel, A.|
|Uncontrolled Keywords||intravital imaging, t cell signalling, multiple sclerosis, experimental autoimmune encephalomyelitis, nicotinic acid adenine dinucleotide phosphate|
|Departments||Faculty of Science > Pharmacy & Pharmacology|
|Publisher Statement||Potter_Brain_2010_133_7_1930.pdf: © The Author(s) 2010. Published by Oxford University Press on behalf of Brain. Distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.5).|
|Additional Information||Funding: This work was supported by the Gemeinnützige Hertie foundation (grant no. 1.01.1/04/010 and 1.01.1/07/005 to A.F. and A.H.G.), the Deutsche Forschungsgemeinschaft (SFB-TR-43 and FOR1336 to A.F., SFB571 to K.D., GU360/7-1,7-2,7-3,7-5 and GU360/13-1 to A.H.G.), the Bundesministerium für Bildung und Forschung (‘Understanding Multiple Sclerosis heterogeneity: linking human disease with animal models—UNDERSTAND MS’ to A.F.), an Enterprise Development Grant from the University of Bath (to B.V.L.P.), and the Wellcome Trust (Biomedical Research Collaboration grant no. 068065 to B.V.L.P. and A.H.G.).|
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