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Submit Manuscript Volume 32, No 1, Jan 2022
ISSN: 1001-0602
EISSN: 1748-7838 2018
impact factor 17.848*
(Clarivate Analytics, 2019)
Volume 32 Issue 1, January 2022: 72-88 |
K2P18.1 translates T cell receptor signals into thymic regulatory T cell development
Tobias Ruck1,2,†,* , Stefanie Bock2,† , Steffen Pfeuffer1 , Christina B. Schroeter11 , Derya Cengiz1,2 , Paul Marciniak1,2 , Maren Lindner2 , Alexander Herrmann1 , Marie Liebmann2 , Stjepana Kovac2 , Lukas Gola2 , Leoni Rolfes1 , Marc Pawlitzki1,2 , Nils Opel3 , Tim Hahn3 , Udo Dannlowski3 , Thomas Pap4 , Felix Luessi5 , Julian A. Schreiber6,7 , 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. Meuth1,2
1Department of Neurology, Medical Faculty, Heinrich-Heine-University, Düsseldorf, GermanyIt 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