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

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.

Visualizing context-dependent calcium signaling in encephalitogenic T cells in vivo by two-photon microscopy

“…5C). Taken together with the observation that BZ194 treatment ameliorates clinical EAE (18), the results suggest that blocking calcium signaling in T cells at this stage can be used as a therapeutic target.…”

“…Thus, the reprogramming of freshly activated T cells to a "migratory" phenotype could be one target along these lines. Indeed, the NAADP antagonist, BZ194, which efficiently blocks intracellular calcium signaling (38), ameliorates clinical EAE both by prophylactic and therapeutic application (18). In this study intravital imaging revealed that BZ194 reduced the frequency of long-lasting calcium signaling in the T cells at the spinal cord leptomeninges (Fig.…”

“…In addition, we applied the nicotinic acid adenine dinucleotide phosphate (NAADP)-antagonist, BZ194, which is known to block the intracellular calcium signaling in vivo and to ameliorate clinical EAE (18). As shown in Fig.…”

Acidic NAADP-sensitive Calcium Stores in the Endothelium

“…The role of NAADP in vivo, however is not known, although a recent study demonstrated that a newly described NAADP antagonist could prevent T cell motility in an animal model of multiple sclerosis (17).…”

The “Other” Inositols and Their Phosphates: Synthesis, Biology, and Medicine (with Recent Advances inmyo‐Inositol Chemistry)

“…SAN 2589 and 4825 blocking cardiac ADP-ribosyl cyclase, [254] that produces the messenger cADPR from NAD, and the considerable success of the NED-19 class of compound where, using computational virtual screening techniques an organic molecule that mimics NAADP and of real biological application was discovered to modulate the activity of the messenger NAADP. [255] Indeed, also, the simple NAADP derivative BZ194 has shown activity in T cells [256], autoimmune disease in vivo [257] and in vivo in the heart. [258] These are promising advances for the idea of pharmacological intervention in second messenger signalling and it should be clear that all of these techniques and ideas that move away from parent polyphosphate structures to more simple and drug-like compounds are in principle applicable to myo-inositol polyphosphates and their various targets, and obviously, perhaps more widely in the inositol series.…”