| 4 | K_(2P)18.1 translates T cell receptor signals into thymic regulatory T cell development显示文摘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(Ca^(2+))is the most important second messenger,for which the potassium channel K_(2P)18.1 is a relevant regulator.Here,we identify K_(2P)18.1 as a central translator of the TCR signal into the thymus-derived Treg(tTreg)selection process.TCR signal was coupled to NF-κB-mediated K_(2P)18.1 upregulation in tTreg progenitors.K_(2P)18.1 provided the driving force for sustained Ca^(2+) influx that facilitated NF-κB-and NFAT-dependent expression of FoxP3,the master transcription factor for Treg development and function.Loss of K_(2P)18.1 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 K_(2P)18.1 resulted in increased Treg numbers in mice.Our findings in human thymus,recent thymic emigrants and multiple sclerosis patients with a dominant-negative missense K_(2P)18.1 variant that is associated with poor clinical outcomes indicate that K_(2P)18.1 also plays a role in human Treg development.Pharmacological modulation of K_(2P)18.1 specifically modulated Treg numbers in vitro and in vivo.Finally,we identified nitroxoline as a K_(2P)18.1 activator that led to rapid and reversible Treg increase in patients with urinary tract infections.Conclusively,our findings reveal how K_(2P)18.1 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. | Tobias Ruck Stefanie Bock Steffen Pfeuffer Christina B.Schroeter Derya Cengiz Paul Marciniak Maren Lindner Alexander Herrmann Marie Liebmann Stjepana Kovac Lukas Gola Leoni Rolfes Marc Pawlitzki Nils Opel Tim Hahn Udo Dannlowski Thomas Pap Felix Luessi Julian A.Schreiber Bernhard Wunsch Tanja Kuhlmann Guiscard Seebohm Bjorn Tackenberg Patricia Seja Frank Doring Erhard Wischmeyer Achmet Imam Chasan Johannes Roth Luisa Klotz Gerd Meyer zu Hörste Heinz Wiendl Tobias Marschall Stefan Floess Jochen Huehn Thomas Budde Tobias Bopp Stefan Bittner Sven G.Meuth | 2022 | Cell Research2022，32，1： | 1 |
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