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K_2P18.1 translates T cell receptor signals into thymic regulatory T cell development

Tobias Ruck^1,2,†,* , Stefanie Bock^2,† , Steffen Pfeuffer¹ , Christina B. Schroeter1¹ , Derya Cengiz^1,2 , Paul Marciniak^1,2 , Maren Lindner² , Alexander Herrmann¹ , Marie Liebmann² , Stjepana Kovac² , Lukas Gola² , Leoni Rolfes¹ , Marc Pawlitzki^1,2 , Nils Opel³ , Tim Hahn³ , Udo Dannlowski³ , Thomas Pap⁴ , Felix Luessi⁵ , Julian A. Schreiber^6,7 , Bernhard Wünsch⁶ , Tanja Kuhlmann⁸ , Guiscard Seebohm⁷ , Björn Tackenberg⁹ , Patricia Seja¹⁰ , Frank Döring¹¹ , Erhard Wischmeyer¹¹ , Achmet Imam Chasan¹² , Johannes Roth¹² , Luisa Klotz² , Gerd Meyer zu Hörste² , Heinz Wiendl² , Tobias Marschall¹³ , Stefan Floess¹⁴ , Jochen Huehn¹⁴ , Thomas Budde¹⁵ , Tobias Bopp¹⁶ , Stefan Bittner⁵ , Sven G. Meuth^1,2

¹Department of Neurology, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany
²Department of Neurology with Institute of Translational Neurology, University of Münster, Münster, Germany
³Institute for Translational Psychiatry, University of Münster, Münster, Germany
⁴Institute of Experimental Musculoskeletal Medicine (IMM), University of Münster, Münster, Germany
⁵Department 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
⁶Institute of Pharmaceutical and Medicinal Chemistry, University of Münster, Münster, Germany
⁷Cellular Electrophysiology and Molecular Biology, Institute for Genetics of Heart Diseases (IfGH), University of Münster, Münster, Germany
⁸Institute of Neuropathology, University of Münster, Münster, Germany
⁹Department of Neurology, Philipps-University, Marburg, Germany
¹⁰Laboratory of Neurobiology, University of Helsinki, Helsinki, Finland
¹¹Molecular Electrophysiology, Institute of Physiology and Center of Mental Health, University of Würzburg, Würzburg, Germany
¹²Institute of Immunology, University of Münster, Münster, Germany
¹³Institute for Medical Biometry and Bioinformatics, Medical Faculty, Heinrich Heine University, Düsseldorf, Germany
¹⁴Department of Experimental Immunology, Helmholtz Centre for Infection Research, Braunschweig, Germany
¹⁵Institute for Physiology I, University of Münster, Münster, Germany
¹⁶Institute of Immunology, Focus Program Immunotherapy (FZI), University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany
^†These authors contributed equally: Tobias Ruck, Stefanie Bock
* Correspondence: Tobias Ruck(tobias.ruck@med.uni-duesseldorf.de)

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 

https://doi.org/10.1038/s41422-021-00580-z

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