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-KB-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.