K2P18.1 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 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.

Dietary regulation in health and disease

“…The K2P18.1 activator nitroxoline is detrimental for urinary tract infections via a rapid and reversible increases in Tregs. 181 Moreover, Se supplementation has been found to enhance GPX4 expression in T cells, increase the numbers of follicular helper T cells and promote antibody responses in mice and humans after influenza vaccination. 182 Similarly, zinc as a dietary supplement stimulates the secretion of bone morphogenetic protein 4 (BMP4) in thymic endothelial cells by binding to its receptor GPR39 to promote T-cell development.…”

The current standing of autologous haematopoietic stem cell transplantation for the treatment of multiple sclerosis

“…In this regard, key factors in the occurrence of relapse are thought to be autoreactivity of IL-17 expressing CD4 + T cells (i.e. T helper 17 cells (T H 17)), CD4 + T helper 1 cells (Th1), CD8 + T cells and the insufficient function of regulatory T cells (T regs) [ 15 – 19 ], indicating that T cells are clearly important in MS pathogenesis. In addition, the recent advent of B cell-targeting monoclonal antibody therapies has established the critical role of, for example, pro-inflammatory CD20-expressing B cells in the cytokine cascade that characterises a relapse [ 20 , 21 ] and daclizumab has more recently demonstrated a role for natural killer (NK) cells [ 22 ].…”

Thinking outside the box: non-canonical targets in multiple sclerosis

“…Recently, the potassium channel K 2P 18.1 has been identified as a critical regulator of thymic T reg cell differentiation. Loss of K 2P 18.1 function reduced T reg cell numbers and worsened EAE 295 . Furthermore, patients with MS who had a dominant-negative missense K 2P 18.1 variant had lower T reg cell numbers and worse clinical outcomes compared to non-carriers.…”

“…Furthermore, patients with MS who had a dominant-negative missense K 2P 18.1 variant had lower T reg cell numbers and worse clinical outcomes compared to non-carriers. Interestingly, pharmacologic activation of K 2P 18.1 rapidly and reversibly increased T reg cell numbers in humans, thus presenting a new potential therapeutic strategy to exploit tolerance induction by T reg cells for the treatment of autoimmune disorders 295 .…”