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Ruck, Tobias; Bock, Stefanie; Pfeuffer, Steffen; Schroeter, Christina B.; Cengiz, Derya; Marciniak, Paul; Lindner, Maren; Herrmann, Alexander; Liebmann, Marie; Kovac, Stjepana; Gola, Lukas; Rolfes, Leoni; Pawlitzki, Marc; Opel, Nils; Hahn, Tim; Dannlowski, Udo; Pap, Thomas; Luessi, Felix; Schreiber, Julian A.; Wünsch, Bernhard; Kuhlmann, Tanja; Seebohm, Guiscard; Tackenberg, Björn; Seja, Patricia; [...]

K2P18.1 translates T cell receptor signals into thymic regulatory T cell development

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  • Media type: E-Article
  • Title: K2P18.1 translates T cell receptor signals into thymic regulatory T cell development
  • Contributor: Ruck, Tobias; Bock, Stefanie; Pfeuffer, Steffen; Schroeter, Christina B.; Cengiz, Derya; Marciniak, Paul; Lindner, Maren; Herrmann, Alexander; Liebmann, Marie; Kovac, Stjepana; Gola, Lukas; Rolfes, Leoni; Pawlitzki, Marc; Opel, Nils; Hahn, Tim; Dannlowski, Udo; Pap, Thomas; Luessi, Felix; Schreiber, Julian A.; Wünsch, Bernhard; Kuhlmann, Tanja; Seebohm, Guiscard; Tackenberg, Björn; Seja, Patricia; [...]
  • Published: Springer Science and Business Media LLC, 2022
  • Published in: Cell Research, 32 (2022) 1, Seite 72-88
  • Language: English
  • DOI: 10.1038/s41422-021-00580-z
  • ISSN: 1001-0602; 1748-7838
  • Origination:
  • Footnote:
  • Description: AbstractIt 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.
  • Access State: Open Access