| Title: |
Multiple signaling events are required for NAADP synthesis by DUOX2 and formation of Ca 2+ microdomains to initiate T cell activation |
| Authors: |
Winterberg, Kai J.; Schwentner, Vanessa; Gu, Feng; Möckl, Franziska; Li, Gaoyang; Bauche, Andreas; Etzold, Stefanie; Rosche, Anette; Weiß, Mariella; Thuille, Nikolaus; Förster, Fritz; Woelk, Lena; Werner, René; Kovacevic, Dejan; Fehse, Boris; Kurelic, Roberta; Nawrocki, Mikolaj; Huber, Samuel; Mittrücker, Hans-Willi; Meier, Chris; Müller, Christa E.; Baier, Gottfried; Skålhegg, Bjørn S.; de Deken, Xavier; Wahl-Schott, Christian; Mair, Thomas; Siebels, Bente; Cugota Canals, Roger; Odoardi, Francesca; Lodygin, Dmitri; Flügel, Alexander; Nikolaev, Viacheslav O.; Diercks, Björn-Philipp; Guse, Andreas H. |
| Contributors: |
European Research Council; Deutsche Forschungsgemeinschaft |
| Source: |
Science Signaling ; volume 19, issue 920 ; ISSN 1945-0877 1937-9145 |
| Publisher Information: |
American Association for the Advancement of Science (AAAS) |
| Publication Year: |
2026 |
| Description: |
T cell activation critically depends on the calcium ion (Ca 2+ )–mobilizing second messenger NAADP (nicotinic acid adenine dinucleotide phosphate), which induces the formation of Ca 2+ microdomains that initiate global Ca 2+ signals. NAADP is produced in immune synapses in T cells by dual NADPH oxidase 2 (DUOX2). Here, we investigated the mechanisms that stimulate DUOX2 activity in T cells. DUOX2 activity was enhanced by a modest increase in intracellular Ca 2+ concentration, similar to that induced by Ca 2+ microdomains that arise in resting T cells through different T cell receptor (TCR)–independent mechanisms. In addition, DUOX2 was activated in vitro by phosphorylation of threonine-789 mediated by PKA Cβ or PKCθ, and genetic deficiency of PKA Cβ2 or PKCθ decreased NAADP-dependent Ca 2+ microdomain formation in T cells. PKA Cβ2 was activated downstream of adenosine A 2A receptors, independently of the TCR. In contrast, PKCθ was activated by the tyrosine kinase LCK downstream of TCR stimulation. Inhibition of A 2A receptors or PKCθ to prevent full DUOX2 activation decreased the production of the proinflammatory cytokine IL-17 by effector T cells. Thus, full stimulation of NAADP signaling that is critical for T cell activation requires integration of multiple TCR-independent and -dependent signals with different spatiotemporal characteristics by DUOX2, a fine-tuning mechanism that could be relevant for inflammation. |
| Document Type: |
article in journal/newspaper |
| Language: |
English |
| DOI: |
10.1126/scisignal.adp4326 |
| Availability: |
https://doi.org/10.1126/scisignal.adp4326; https://www.science.org/doi/pdf/10.1126/scisignal.adp4326 |
| Accession Number: |
edsbas.CDB65266 |
| Database: |
BASE |