Journal
CELL RESEARCH
Volume 32, Issue 1, Pages 72-88Publisher
SPRINGERNATURE
DOI: 10.1038/s41422-021-00580-z
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Funding
- Interdisciplinary Center for Clinical Research (IZKF) of the Medical Faculty of Munster [Dan3/012/17]
- Deutsche Forschungsgemeinschaft [SFB BI1822/1-1, CRC-TR-128, RTG 2515]
- Else Kroner-Fresenius-Stiftung [2018_A03]
- Hertie Foundation
- Graduate School of the Cells-in-Motion Cluster of Excellence, University of Munster, Germany [EXC 1003-CiM]
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This study reveals how K(2P)18.1 translates TCR signals into thymic T cell fate decisions and Treg development, as well as its role in human Treg development. The findings provide a basis for therapeutic utilization of Treg in several human disorders.
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 K(2P)18.1 is a relevant regulator. Here, we identify K(2P)18.1 as a central translator of the TCR signal into the thymus-derived Treg (tTreg) selection process. TCR signal was coupled to NF-kappa B-mediated K(2P)18.1 upregulation in tTreg progenitors. K(2P)18.1 provided the driving force for sustained Ca2+ influx that facilitated NF-kappa B- and NFAT-dependent expression of FoxP3, the master transcription factor for Treg development and function. Loss of K(2P)18.1 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 K(2P)18.1 resulted in increased Treg numbers in mice. Our findings in human thymus, recent thymic emigrants and multiple sclerosis patients with a dominant-negative missense K(2P)18.1 variant that is associated with poor clinical outcomes indicate that K(2P)18.1 also plays a role in human Treg development. Pharmacological modulation of K(2P)18.1 specifically modulated Treg numbers in vitro and in vivo. Finally, we identified nitroxoline as a K(2P)18.1 activator that led to rapid and reversible Treg increase in patients with urinary tract infections. Conclusively, our findings reveal how K(2P)18.1 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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