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

Date Published: January 20, 2017

Publisher: Public Library of Science

Author(s): Wai-Ping Fung-Leung, Wilson Edwards, Yi Liu, Karen Ngo, Julianty Angsana, Glenda Castro, Nancy Wu, Xuejun Liu, Ronald V. Swanson, Alan D. Wickenden, Troy A Baldwin.

http://doi.org/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.

Partial Text

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, 3–8]. 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 [10–12]. NFAT pathway is a calcium dependent signaling pathway that requires a sustained calcium flux to activate the phosphatase calcineurin and the downstream transcription factor NFAT for induction of gene expression [13–15]. Calcium mobilization in T cells is mediated by the store-operated calcium channel known as calcium release activated calcium (CRAC) channel, which is recruited to the immunological synapse upon TCR engagement [16]. Kv1.3 is also recruited to the immunological synapse and is thought to be required for sustaining the CRAC mediated calcium flux [3, 7, 17–19].

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. In order to better understand this potential however, more information is needed on the activity profile of Kv1.3 blockers across various T cell subsets, and disease relevant T cells, under a range of stimulation conditions.

 

Source:

http://doi.org/10.1371/journal.pone.0170102

 

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