Human T cells in silico: Modelling dynamic intracellular calcium and its influence on cellular electrophysiology

Eichinger, Paul; Herrmann, Alexander M.; Ruck, Tobias; Herty, Michaël; Gola, Lukas; Kovač, Stjepana; Budde, Thomas; Meuth, Sven G.; Hundehege, Petra

doi:10.1016/j.jim.2018.06.020

Cited by 12 publications

(11 citation statements)

References 41 publications

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“…However, in comparison to conventional T cells (~-47mV), Tregs reveal a hyperpolarized membrane potential around -70 mV, suggesting additional or altered ion fluxes [11]. As the resting membrane potential of a cell is due to the outward diffusion of potassium ions, the closer examination of voltage-and calcium-gated K 2P channels (e.g., TRESK and TASK subfamilies) in Tregs could be worthwhile [87]. Accordingly, an in-silico model of human T cell electrophysiological behavior takes the contribution of further ion channels into account and highlights their impact on physiological and pathological conditions [88].…”

Section: Discussionmentioning

confidence: 99%

Impact of Diverse Ion Channels on Regulatory T Cell Functions

Vinnenberg

Böck

Hundehege

et al. 2021

Cell Physiol Biochem

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The population of regulatory T cells (Tregs) is critical for immunological self-tolerance and homeostasis. Proper ion regulation contributes to Treg lineage identity, regulation, and effector function. Identified ion channels include Ca2+ release-activated Ca2+, transient receptor potential, P2X, volume-regulated anion and K+ channels Kv1.3 and KCa3.1. Ion channel modulation represents a promising therapeutic approach for the treatment of autoimmune diseases such as rheumatoid arthritis and multiple sclerosis. This review summarizes studies with gene-targeted mice and pharmacological modulators affecting Treg number and function. Furthermore, participation of ion channels is illustrated and the power of future research possibilities is discussed.

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Section: Discussionmentioning

confidence: 99%

Impact of Diverse Ion Channels on Regulatory T Cell Functions

Vinnenberg

Böck

Hundehege

et al. 2021

Cell Physiol Biochem

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“…As potassium (K + ) channels are the driving force for sustained Ca 2+ influx by mediating a hyperpolarizing outward current, they represent likely candidates that are involved in these processes. 17 , 18 In the family of K + channels, two-pore domain K + (K 2P ) channels are especially suited to serve as such a regulatory factor for tTreg development as they are major determinants of K + conductance, adjust excitability and counteract membrane potential depolarization. Moreover, K 2P channels are regulated by various extra- and intracellular stimuli, thereby integrating diverse signals in multiple circumstances ranging from basic cellular functions to complex pathogenic processes.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2021

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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.

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“…the modulation of the membrane potential and cell secretion by single ion channels, calcium dynamics or activation of T-lymphocytes. [39][40][41][42] The A549 cell line, derived from non-small cell lung cancer (NSCLC), is a widely used model for studying lung cancer and cancer drug development. [43][44][45] In this work we introduce for the first time an ion current model of the A549 human lung adenocarcinoma cell, representing an initial description of a cell model as a whole in cancer electrophysiology.…”

Section: Introductionmentioning

confidence: 99%

A549 in-silico 1.0: A first computational model to simulate cell cycle dependent ion current modulation in the human lung adenocarcinoma

et al. 2021

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Lung cancer is still a leading cause of death worldwide. In recent years, knowledge has been obtained of the mechanisms modulating ion channel kinetics and thus of cell bioelectric properties, which is promising for oncological biomarkers and targets. The complex interplay of channel expression and its consequences on malignant processes, however, is still insufficiently understood. We here introduce the first approach of an in-silico whole-cell ion current model of a cancer cell, in particular of the A549 human lung adenocarcinoma, including the main functionally expressed ion channels in the plasma membrane as so far known. This hidden Markov-based model represents the electrophysiology behind proliferation of the A549 cell, describing its rhythmic oscillation of the membrane potential able to trigger the transition between cell cycle phases, and it predicts membrane potential changes over the cell cycle provoked by targeted ion channel modulation. This first A549 in-silico cell model opens up a deeper insight and understanding of possible ion channel interactions in tumor development and progression, and is a valuable tool for simulating altered ion channel function in lung cancer electrophysiology.

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Human T cells in silico: Modelling dynamic intracellular calcium and its influence on cellular electrophysiology

Cited by 12 publications

References 41 publications

Impact of Diverse Ion Channels on Regulatory T Cell Functions

Impact of Diverse Ion Channels on Regulatory T Cell Functions

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

A549 in-silico 1.0: A first computational model to simulate cell cycle dependent ion current modulation in the human lung adenocarcinoma

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