Untitled
dc.contributor.author | Ruck, Tobias | |
dc.contributor.author | Bock, Stefanie | |
dc.contributor.author | Pfeuffer, Steffen | |
dc.contributor.author | Schroeter, Christina B | |
dc.contributor.author | Cengiz, Derya | |
dc.contributor.author | Marciniak, Paul | |
dc.contributor.author | Lindner, Maren | |
dc.contributor.author | Herrmann, Alexander | |
dc.contributor.author | Liebmann, Marie | |
dc.contributor.author | Kovac, Stjepana | |
dc.contributor.author | Gola, Lukas | |
dc.contributor.author | Rolfes, Leoni | |
dc.contributor.author | Pawlitzki, Marc | |
dc.contributor.author | Opel, Nils | |
dc.contributor.author | Hahn, Tim | |
dc.contributor.author | Dannlowski, Udo | |
dc.contributor.author | Pap, Thomas | |
dc.contributor.author | Luessi, Felix | |
dc.contributor.author | Schreiber, Julian A | |
dc.contributor.author | Wünsch, Bernhard | |
dc.contributor.author | Kuhlmann, Tanja | |
dc.contributor.author | Seebohm, Guiscard | |
dc.contributor.author | Tackenberg, Björn | |
dc.contributor.author | Seja, Patricia | |
dc.contributor.author | Döring, Frank | |
dc.contributor.author | Wischmeyer, Erhard | |
dc.contributor.author | Chasan, Achmet Imam | |
dc.contributor.author | Roth, Johannes | |
dc.contributor.author | Klotz, Luisa | |
dc.contributor.author | Meyer Zu Hörste, Gerd | |
dc.contributor.author | Wiendl, Heinz | |
dc.contributor.author | Marschall, Tobias | |
dc.contributor.author | Floess, Stefan | |
dc.contributor.author | Huehn, Jochen | |
dc.contributor.author | Budde, Thomas | |
dc.contributor.author | Bopp, Tobias | |
dc.contributor.author | Bittner, Stefan | |
dc.contributor.author | Meuth, Sven G | |
dc.date.accessioned | 2022-01-11T15:58:43Z | |
dc.date.available | 2022-01-11T15:58:43Z | |
dc.date.issued | 2021-10-26 | |
dc.identifier.citation | Cell Res. 2022 Jan;32(1):72-88. doi: 10.1038/s41422-021-00580-z. Epub 2021 Oct 26. PMID: 34702947. | en_US |
dc.identifier.pmid | 34702947 | |
dc.identifier.doi | 10.1038/s41422-021-00580-z | |
dc.identifier.uri | http://hdl.handle.net/10033/623138 | |
dc.description.abstract | It 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.language.iso | en | en_US |
dc.publisher | Springer Nature | en_US |
dc.rights | Attribution-ShareAlike 4.0 International | * |
dc.rights.uri | http://creativecommons.org/licenses/by-sa/4.0/ | * |
dc.type | Article | en_US |
dc.identifier.eissn | 1748-7838 | |
dc.contributor.department | HZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany. | en_US |
dc.identifier.journal | Cell research | en_US |
dc.source.volume | 32 | |
dc.source.issue | 1 | |
dc.source.beginpage | 72 | |
dc.source.endpage | 88 | |
refterms.dateFOA | 2022-01-11T15:58:43Z | |
dc.source.journaltitle | Cell research | |
dc.source.country | England |