Nicotinic acid adenine dinucleotide phosphate-mediated calcium signalling in effector T cells regulates autoimmunity of the central nervous system

Chiara Cordiglieri, Francesca Odoardi, Bo Zhang, Merle Nebel, Naoto Kawakami, Wolfgang E F Klinkert, Dimtri Lodygin, Fred Lühder, Esther Breunig, Detlev Schild, Vijay Kumar Ulaganathan, Klaus Dornmair, Werner Dammermann, Barry V L Potter, Andreas H. Guse, Alexander Flügel

Research output: Contribution to journalArticle

35 Citations (Scopus)

Abstract

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. Naïve 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.

Original languageEnglish
Pages (from-to)1930-1943
Number of pages14
JournalBrain
Volume133
Issue number7
DOIs
Publication statusPublished - Jul 2010

Fingerprint

Calcium Signaling
Autoimmunity
Central Nervous System
T-Lymphocytes
Ryanodine Receptor Calcium Release Channel
Autoimmune Experimental Encephalomyelitis
NAADP
Cytokines
Nerve Tissue
Antigen Receptors
Molecular Imaging
Interleukin-17
Niacin
Second Messenger Systems
Photons
Autoimmune Diseases
Interferon-gamma
Multiple Sclerosis
Cell Movement
Animal Models

Keywords

  • experimental autoimmune encephalomyelitis
  • intravital imaging
  • multiple sclerosis
  • nicotinic acid adenine dinucleotide phosphate
  • T cell signalling

ASJC Scopus subject areas

  • Clinical Neurology

Cite this

Cordiglieri, C., Odoardi, F., Zhang, B., Nebel, M., Kawakami, N., Klinkert, W. E. F., ... Flügel, A. (2010). Nicotinic acid adenine dinucleotide phosphate-mediated calcium signalling in effector T cells regulates autoimmunity of the central nervous system. Brain, 133(7), 1930-1943. https://doi.org/10.1093/brain/awq135

Nicotinic acid adenine dinucleotide phosphate-mediated calcium signalling in effector T cells regulates autoimmunity of the central nervous system. / Cordiglieri, Chiara; Odoardi, Francesca; Zhang, Bo; Nebel, Merle; Kawakami, Naoto; Klinkert, Wolfgang E F; Lodygin, Dimtri; Lühder, Fred; Breunig, Esther; Schild, Detlev; Ulaganathan, Vijay Kumar; Dornmair, Klaus; Dammermann, Werner; Potter, Barry V L; Guse, Andreas H.; Flügel, Alexander.

In: Brain, Vol. 133, No. 7, 07.2010, p. 1930-1943.

Research output: Contribution to journalArticle

Cordiglieri, C, Odoardi, F, Zhang, B, Nebel, M, Kawakami, N, Klinkert, WEF, Lodygin, D, Lühder, F, Breunig, E, Schild, D, Ulaganathan, VK, Dornmair, K, Dammermann, W, Potter, BVL, Guse, AH & Flügel, A 2010, 'Nicotinic acid adenine dinucleotide phosphate-mediated calcium signalling in effector T cells regulates autoimmunity of the central nervous system', Brain, vol. 133, no. 7, pp. 1930-1943. https://doi.org/10.1093/brain/awq135
Cordiglieri, Chiara ; Odoardi, Francesca ; Zhang, Bo ; Nebel, Merle ; Kawakami, Naoto ; Klinkert, Wolfgang E F ; Lodygin, Dimtri ; Lühder, Fred ; Breunig, Esther ; Schild, Detlev ; Ulaganathan, Vijay Kumar ; Dornmair, Klaus ; Dammermann, Werner ; Potter, Barry V L ; Guse, Andreas H. ; Flügel, Alexander. / Nicotinic acid adenine dinucleotide phosphate-mediated calcium signalling in effector T cells regulates autoimmunity of the central nervous system. In: Brain. 2010 ; Vol. 133, No. 7. pp. 1930-1943.
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