1. K2P18.1 translates T cell receptor signals into thymic regulatory T cell development
- Author
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Maren Lindner, Tobias Bopp, Stefanie Bock, Steffen Pfeuffer, Felix Luessi, Sven G. Meuth, Jochen Huehn, Thomas Pap, Marc Pawlitzki, Stefan Bittner, Marie Liebmann, Paul Marciniak, Leoni Rolfes, Stjepana Kovac, Johannes Roth, Gerd Meyer zu Hörste, Nils Opel, Patricia Seja, Derya Cengiz, Alexander M Herrmann, Achmet Imam Chasan, Stefan Floess, Tim Hahn, Luisa Klotz, Tobias Marschall, Björn Tackenberg, Erhard Wischmeyer, Thomas Budde, Julian A. Schreiber, Udo Dannlowski, Bernhard Wünsch, Tanja Kuhlmann, Christina B Schroeter, Heinz Wiendl, Tobias Ruck, Frank Döring, Guiscard Seebohm, Lukas Gola, Basal ganglia circuits, and Molecular and Integrative Biosciences Research Programme
- Subjects
EXPRESSION ,TRESK ,Regulatory T cell ,T cell ,NF-KAPPA-B ,Receptors, Antigen, T-Cell ,DEPENDENT ACTIVATION ,Autoimmunity ,chemical and pharmacologic phenomena ,Thymus Gland ,Cell fate determination ,Biology ,T-Lymphocytes, Regulatory ,Article ,CALCIUM ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Downregulation and upregulation ,otorhinolaryngologic diseases ,ION CHANNELS ,medicine ,Animals ,Humans ,Progenitor cell ,Molecular Biology ,030304 developmental biology ,0303 health sciences ,Thymocytes ,Calcium signalling ,Experimental autoimmune encephalomyelitis ,T-cell receptor ,NF-kappa B ,FOXP3 ,Cell Differentiation ,Forkhead Transcription Factors ,hemic and immune systems ,Cell Biology ,medicine.disease ,3. Good health ,DIFFERENTIATION ,medicine.anatomical_structure ,NUCLEAR FACTOR ,K+ CHANNEL ,Cancer research ,1182 Biochemistry, cell and molecular biology ,Ion channel signalling ,POTASSIUM CHANNELS ,030217 neurology & neurosurgery - Abstract
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 basis for the therapeutic utilization of Treg in several human disorders.
- Published
- 2021