{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,28]],"date-time":"2026-07-28T14:12:16Z","timestamp":1785247936513,"version":"3.55.0"},"reference-count":66,"publisher":"American Association for the Advancement of Science (AAAS)","issue":"920","funder":[{"DOI":"10.13039\/501100000781","name":"European Research Council","doi-asserted-by":"publisher","award":["786462"],"award-info":[{"award-number":["786462"]}],"id":[{"id":"10.13039\/501100000781","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["335447717"],"award-info":[{"award-number":["335447717"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.science.org"],"crossmark-restriction":true},"short-container-title":["Sci. Signal."],"published-print":{"date-parts":[[2026,1,13]]},"abstract":"<jats:p>\n                    T cell activation critically depends on the calcium ion (Ca\n                    <jats:sup>2+<\/jats:sup>\n                    )\u2013mobilizing second messenger NAADP (nicotinic acid adenine dinucleotide phosphate), which induces the formation of Ca\n                    <jats:sup>2+<\/jats:sup>\n                    microdomains that initiate global Ca\n                    <jats:sup>2+<\/jats:sup>\n                    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\n                    <jats:sup>2+<\/jats:sup>\n                    concentration, similar to that induced by Ca\n                    <jats:sup>2+<\/jats:sup>\n                    microdomains that arise in resting T cells through different T cell receptor (TCR)\u2013independent mechanisms. In addition, DUOX2 was activated in vitro by phosphorylation of threonine-789 mediated by PKA C\u03b2 or PKC\u03b8, and genetic deficiency of PKA C\u03b22 or PKC\u03b8 decreased NAADP-dependent Ca\n                    <jats:sup>2+<\/jats:sup>\n                    microdomain formation in T cells. PKA C\u03b22 was activated downstream of adenosine A\n                    <jats:sub>2A<\/jats:sub>\n                    receptors, independently of the TCR. In contrast, PKC\u03b8 was activated by the tyrosine kinase LCK downstream of TCR stimulation. Inhibition of A\n                    <jats:sub>2A<\/jats:sub>\n                    receptors or PKC\u03b8 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.\n                  <\/jats:p>","DOI":"10.1126\/scisignal.adp4326","type":"journal-article","created":{"date-parts":[[2026,1,13]],"date-time":"2026-01-13T18:58:12Z","timestamp":1768330692000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":3,"title":["Multiple signaling events are required for NAADP synthesis by DUOX2 and formation of Ca\n                    <sup>2+<\/sup>\n                    microdomains to initiate T cell activation"],"prefix":"10.1126","volume":"19","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5126-5525","authenticated-orcid":true,"given":"Kai J.","family":"Winterberg","sequence":"first","affiliation":[{"name":"Calcium Signalling 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