K2P18.1 translates T cell receptor signals into thymic regulatory T cell development

• 作者: Tobias Ruck Stefanie Bock Steffen Pfeuffer Christina B.Schroeter Derya Cengiz Paul Marciniak Maren Lindner Alexander Herrmann Marie Liebmann Stjepana Kovac Lukas Gola Leoni Rolfes Marc Pawlitzki Nils Opel Tim Hahn Udo Dannlowski Thomas Pap Felix Luessi Julian A.Schreiber Bernhard Wünsch Tanja Kuhlmann Guiscard Seebohm Bj(o)rn Tackenberg Patricia Seja Frank D(o)ring Erhard Wischmeyer Achmet Imam Chasan Johannes Roth Luisa Klotz Gerd Meyer zu H(o)rste Heinz Wiendl Tobias Marschall Stefan Floess Jochen Huehn Thomas Budde Tobias Bopp Stefan Bittner Sven G.Meuth
• 来源期刊: 细胞研究（英文版）
• 年，卷（期）: 2022,（1）
• 所属期刊栏目: ARTICLES
• 页码范围: 72-88
• 页数: 17页
• 语种: 英文

摘要

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.