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-KB-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.

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 Wünsch;Tanja Kuhlmann;Guiscard Seebohm;Bj(o)rn Tackenberg;Patricia Seja;Frank D(o)ring;Erhard Wischmeyer;Achmet Imam Chasan;Johannes Roth;Luisa Klotz;Gerd Meyer zu H(o)rste;Heinz Wiendl;Tobias Marschall;Stefan Floess;Jochen Huehn;Thomas Budde;Tobias Bopp;Stefan Bittner;Sven G.Meuth

Department of Neurology,Medical Faculty,Heinrich-Heine-University,Düsseldorf,Germany;Department of Neurology with Institute of Translational Neurology,University of Münster,Münster,Germany;Institute for Translational Psychiatry,University of Münster,Münster,Germany;Institute of Experimental Musculoskeletal Medicine (IMM),University of Münster,Münster,Germany;Department of Neurology,Focus Program Translational Neuroscience (FTN) and Immunotherapy (FZI),Rhine Main Neuroscience Network (rmn2 ,University Medical Center of the Johannes Gutenberg University Mainz,Mainz,Germany;Institute of Pharmaceutical and Medicinal Chemistry,University of Münster,Münster,Germany;Cellular Electrophysiology and Molecular Biology,Institute for Genetics of Heart Diseases (IfGH),University of Münster,Münster,Germany;Institute of Neuropathology,University of Münster,Münster,Germany;Department of Neurology,Philipps-University,Marburg,Germany;Laboratory of Neurobiology,University of Helsinki,Helsinki,Finland;Molecular Electrophysiology,Institute of Physiology and Center of Mental Health,University of Würzburg,Würzburg,Germany;Institute of Immunology,University of Münster,Münster,Germany;Institute for Medical Biometry and Bioinformatics,Medical Faculty,Heinrich Heine University,Düsseldorf,Germany;Department of Experimental Immunology,Helmholtz Centre for Infection Research,Braunschweig,Germany;Institute for Physiology I,University of Münster,Münster,Germany;Institute of Immunology,Focus Program Immunotherapy (FZI),University Medical Center of the Johannes Gutenberg University Mainz,Mainz,Germany

细胞研究（英文版）

[1]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 Wünsch;Tanja Kuhlmann;Guiscard Seebohm;Bj(o)rn Tackenberg;Patricia Seja;Frank D(o)ring;Erhard Wischmeyer;Achmet Imam Chasan;Johannes Roth;Luisa Klotz;Gerd Meyer zu H(o)rste;Heinz Wiendl;Tobias Marschall;Stefan Floess;Jochen Huehn;Thomas Budde;Tobias Bopp;Stefan Bittner;Sven G.Meuth-.K2P18.1 translates T cell receptor signals into thymic regulatory T cell development)[J].细胞研究（英文版）,2022(01):72-88

K2P18,thymocytes,Tconv,tTreg,emigrants,nitroxoline

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