T Cell Subset and Stimulation Strength-Dependent Modulation of T Cell Activation by Kv1.3 Blockers.

Wilson Edwards,Nancy Wu,Karen Ngo,Yi Liu,Glenda Castro,Julianty Angsana,Alan D. Wickenden,Wai-Ping Fung-Leung,Ronald V. Swanson,Xuejun Liu

doi:10.1371/journal.pone.0170102

Abstract

Kv1.3 is a voltage-gated potassium channel expressed on T cells that plays an important role in T cell activation. Previous studies have shown that blocking Kv1.3 channels in human T cells during activation results in reduced calcium entry, cytokine production, and proliferation. The aim of the present study was to further explore the effects of Kv1.3 blockers on the response of different human T cell subsets under various stimulation conditions. Our studies show that, unlike the immune suppressor cyclosporine A, the inhibitory effect of Kv1.3 blockers was partial and stimulation strength dependent, with reduced inhibitory efficacy on T cells under strengthened anti-CD3/CD28 stimulations. T cell responses to allergens including house dust mites and ragweed were partially reduced by Kv1.3 blockers. The effect of Kv1.3 inhibition was dependent on T cell subsets, with stronger effects on CCR7- effector memory compared to CCR7+ central memory CD4 T cells. Calcium entry studies also revealed a population of CD4 T cells resistant to Kv1.3 blockade. Activation of CD4 T cells was accompanied with an increase in Kv1.3 currents but Kv1.3 transcripts were found to be reduced, suggesting a posttranscriptional mechanism in the regulation of Kv1.3 activities. In summary, Kv1.3 blockers inhibit T cell activation in a manner that is highly dependent on the T cell identity and stimulation strength, These findings suggest that Kv1.3 blockers inhibit T cells in a unique, conditional manner, further refining our understanding of the therapeutic potential of Kv1.3 blockers.

Highlights

Kv1.3 is a voltage-gated potassium channel (Kv) which opens in response to membrane depolarization [1]
Kv1.3 is known to play a role in modulating T cell activation [3, 41] and Kv1.3 blockers may have potential therapeutic effect on treatment of autoimmune diseases
We and others show that calcium fluxes induced by coupling of TCR and CD28 with antibodies, or by thapsigargin treatment, were only partially inhibited by Kv1.3 blockers [42]

Summary

Introduction

Kv1.3 is a voltage-gated potassium channel (Kv) which opens in response to membrane depolarization [1]. Functional Kv1.3 is comprised of a homotetramer of pore forming alpha subunits and membrane depolarization is sensed by positively charged arginine residues in the fourth transmembrane region of each subunit [2]. Kv1.3 has been suggested to play a role in T cell activation [1, 3,4,5,6,7,8]. T cells are activated through TCR (T cell receptor) engagement with specific antigenic peptides presented by self MHC molecules on antigen presenting cells [9]. Multiple signaling cascades including MAPK, NF-kB and NFAT pathways are activated by the TCR complex [10,11,12]. NFAT pathway is a calcium dependent signaling pathway that requires

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