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dc.contributor.authorRuck, Tobias
dc.contributor.authorBock, Stefanie
dc.contributor.authorPfeuffer, Steffen
dc.contributor.authorSchroeter, Christina B
dc.contributor.authorCengiz, Derya
dc.contributor.authorMarciniak, Paul
dc.contributor.authorLindner, Maren
dc.contributor.authorHerrmann, Alexander
dc.contributor.authorLiebmann, Marie
dc.contributor.authorKovac, Stjepana
dc.contributor.authorGola, Lukas
dc.contributor.authorRolfes, Leoni
dc.contributor.authorPawlitzki, Marc
dc.contributor.authorOpel, Nils
dc.contributor.authorHahn, Tim
dc.contributor.authorDannlowski, Udo
dc.contributor.authorPap, Thomas
dc.contributor.authorLuessi, Felix
dc.contributor.authorSchreiber, Julian A
dc.contributor.authorWünsch, Bernhard
dc.contributor.authorKuhlmann, Tanja
dc.contributor.authorSeebohm, Guiscard
dc.contributor.authorTackenberg, Björn
dc.contributor.authorSeja, Patricia
dc.contributor.authorDöring, Frank
dc.contributor.authorWischmeyer, Erhard
dc.contributor.authorChasan, Achmet Imam
dc.contributor.authorRoth, Johannes
dc.contributor.authorKlotz, Luisa
dc.contributor.authorMeyer Zu Hörste, Gerd
dc.contributor.authorWiendl, Heinz
dc.contributor.authorMarschall, Tobias
dc.contributor.authorFloess, Stefan
dc.contributor.authorHuehn, Jochen
dc.contributor.authorBudde, Thomas
dc.contributor.authorBopp, Tobias
dc.contributor.authorBittner, Stefan
dc.contributor.authorMeuth, Sven G
dc.identifier.citationCell Res. 2022 Jan;32(1):72-88. doi: 10.1038/s41422-021-00580-z. Epub 2021 Oct 26. PMID: 34702947.en_US
dc.description.abstractIt remains largely unclear how thymocytes translate relative differences in T cell receptor (TCR) signal strength into distinct developmental programs that drive the cell fate decisions towards conventional (Tconv) or regulatory T cells (Treg). Following TCR activation, intracellular calcium (Ca2+) is the most important second messenger, for which the potassium channel K2P18.1 is a relevant regulator. Here, we identify K2P18.1 as a central translator of the TCR signal into the thymus-derived Treg (tTreg) selection process. TCR signal was coupled to NF-κB-mediated K2P18.1 upregulation in tTreg progenitors. K2P18.1 provided the driving force for sustained Ca2+ influx that facilitated NF-κB- and NFAT-dependent expression of FoxP3, the master transcription factor for Treg development and function. Loss of K2P18.1 ion-current function induced a mild lymphoproliferative phenotype in mice, with reduced Treg numbers that led to aggravated experimental autoimmune encephalomyelitis, while a gain-of-function mutation in K2P18.1 resulted in increased Treg numbers in mice. Our findings in human thymus, recent thymic emigrants and multiple sclerosis patients with a dominant-negative missense K2P18.1 variant that is associated with poor clinical outcomes indicate that K2P18.1 also plays a role in human Treg development. Pharmacological modulation of K2P18.1 specifically modulated Treg numbers in vitro and in vivo. Finally, we identified nitroxoline as a K2P18.1 activator that led to rapid and reversible Treg increase in patients with urinary tract infections. Conclusively, our findings reveal how K2P18.1 translates TCR signals into thymic T cell fate decisions and Treg development, and provide a basis for the therapeutic utilization of Treg in several human disorders.en_US
dc.publisherSpringer Natureen_US
dc.rightsAttribution-ShareAlike 4.0 International*
dc.contributor.departmentHZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany.en_US
dc.identifier.journalCell researchen_US
dc.source.journaltitleCell research

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