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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
Ruck, Tobias
Bock, Stefanie
Pfeuffer, Steffen
Schroeter, Christina B
Cengiz, Derya
Marciniak, Paul
Lindner, Maren
Herrmann, Alexander
Liebmann, Marie
Kovac, Stjepana
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2021-10-26
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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.
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Cell Res. 2022 Jan;32(1):72-88. doi: 10.1038/s41422-021-00580-z. Epub 2021 Oct 26. PMID: 34702947.
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en
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1748-7838
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Attribution-ShareAlike 4.0 International