K_2P18.1 translates T cell receptor signals into thymic regulatory T cell development.

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 K_2P18.1 is a relevant regulator. Here, we identify K_2P18.1 as a central translator of the TCR signal into the thymus-derived Treg (tTreg) selection process. TCR signal was coupled to NF-κB-mediated K_2P18.1 upregulation in tTreg progenitors. K_2P18.1 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 K_2P18.1 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_2P18.1 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_2P18.1 variant that is associated with poor clinical outcomes indicate that K_2P18.1 also plays a role in human Treg development. Pharmacological modulation of K_2P18.1 specifically modulated Treg numbers in vitro and in vivo. Finally, we identified nitroxoline as a K_2P18.1 activator that led to rapid and reversible Treg increase in patients with urinary tract infections. Conclusively, our findings reveal how K_2P18.1 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.

SUBMITTER: Ruck T 

PROVIDER: S-EPMC8547300 | biostudies-literature | 2022 Jan

REPOSITORIES: biostudies-literature