title: T Cell Subset and Stimulation Strength-Dependent Modulation of T Cell Activation by Kv1.3 Blockers.
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.
authors.affiliation: Janssen Research & Development, L.L.C., San Diego, California, United States of America.
authors.forename: Wai-Ping
authors.initials: WP
authors.lastname: Fung-Leung
authors.affiliation: Janssen Research & Development, L.L.C., San Diego, California, United States of America.
authors.forename: Wilson
authors.initials: W
authors.lastname: Edwards
authors.affiliation: Janssen Research & Development, L.L.C., San Diego, California, United States of America.
authors.forename: Yi
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Janssen Research & Development, L.L.C., San Diego, California, United States of America.
authors.forename: Karen
authors.initials: K
authors.lastname: Ngo
authors.affiliation: Janssen Research & Development, L.L.C., San Diego, California, United States of America.
authors.forename: Julianty
authors.initials: J
authors.lastname: Angsana
authors.affiliation: Janssen Research & Development, L.L.C., San Diego, California, United States of America.
authors.forename: Glenda
authors.initials: G
authors.lastname: Castro
authors.affiliation: Janssen Research & Development, L.L.C., San Diego, California, United States of America.
authors.forename: Nancy
authors.initials: N
authors.lastname: Wu
authors.affiliation: Janssen Research & Development, L.L.C., San Diego, California, United States of America.
authors.forename: Xuejun
authors.initials: X
authors.lastname: Liu
authors.affiliation: Janssen Research & Development, L.L.C., San Diego, California, United States of America.
authors.forename: Ronald V
authors.initials: RV
authors.lastname: Swanson
authors.affiliation: Janssen Research & Development, L.L.C., San Diego, California, United States of America.
authors.forename: Alan D
authors.initials: AD
authors.lastname: Wickenden
mesh_terms: D020869:Gene Expression Profiling; D006801:Humans; D051664:Kv1.3 Potassium Channel / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D008213:Lymphocyte Activation; D018408:Patch-Clamp Techniques; D026902:Potassium Channel Blockers / Q000494:pharmacology*; D016176:T-Lymphocyte Subsets; D013601:T-Lymphocytes / Q000276:immunology*
chemical_list: D051664:Kv1.3 Potassium Channel; D026902:Potassium Channel Blockers