title: Normal human CD4(+) helper T cells express Kv1.1 voltage-gated K(+) channels, and selective Kv1.1 block in T cells induces by itself robust TNFα production and secretion and activation of the NFκB non-canonical pathway.
abstract: TNFα is a very potent and pleiotropic pro-inflammatory cytokine, essential to the immune system for eradicating cancer and microorganisms, and to the nervous system, for brain development and ongoing function. Yet, excess and/or chronic TNFα secretion causes massive tissue damage in autoimmune, inflammatory and neurological diseases and injuries. Therefore, many patients with autoimmune/inflammatory diseases receive anti-TNFα medications. TNFα is secreted primarily by CD4(+) T cells, macrophages, monocytes, neutrophils and NK cells, mainly after immune stimulation. Yet, the cause for the pathologically high and chronic TNFα secretion is unknown. Can blocking of a particular ion channel in T cells induce by itself TNFα secretion? Such phenomenon was never revealed or even hypothesized. In this interdisciplinary study we discovered that: (1) normal human T cells express Kv1.1 voltage-gated potassium channel mRNA, and the Kv1.1 membrane-anchored protein channel; (2) Kv1.1 is expressed in most CD4(+)CD3(+) helper T cells (mean CD4(+)CD3(+)Kv1.1(+) T cells of 7 healthy subjects: 53.09 ± 22.17 %), but not in CD8(+)CD3(+) cytotoxic T cells (mean CD8(+)CD3(+)Kv1.1(+) T cells: 4.12 ± 3.04 %); (3) electrophysiological whole-cell recordings in normal human T cells revealed Kv currents; (4) Dendrotoxin-K (DTX-K), a highly selective Kv1.1 blocker derived from snake toxin, increases the rate of rise and decay of Kv currents in both resting and activated T cells, without affecting the peak current; (5) DTX-K by itself induces robust TNFα production and secretion by normal human T cells, without elevating IFNγ, IL-4 and IL-10; (6) intact Ca(2+) channels are required for DTX-induced TNFα secretion; (7) selective anti-Kv1.1 antibodies also induce by themselves TNFα secretion; (8) DTX-K activates NFκB in normal human T cells via the unique non-canonical-pathway; (9) injection of Kv1.1-blocked human T cells to SCID mice, causes recruitment of resident mouse cells into the liver, alike reported after TNFα injection into the brain. Based on our discoveries we speculate that abnormally blocked Kv1.1 in T cells (and other immune cells?), due to either anti-Kv1.1 autoimmune antibodies, or Kv1.1-blocking toxins alike DTX-K, or Kv1.1-blocking genetic mutations, may be responsible for the chronic/excessive TNFα in autoimmune/inflammatory diseases. Independently, we also hypothesize that selective block of Kv1.1 in CD4(+) T cells of patients with cancer or chronic infectious diseases could be therapeutic, since it may: a. augment beneficial secretion and delivery of TNFα to the disease-affected sites; b. induce recruitment and extravasation of curative immune cells and factors; c. improve accessibility of drugs to the brain and few peripheral organs thanks to TNFα-induced increased permeability of organ's barriers.
authors.affiliation: Immunis e.V. and Immunotherapy Research Center, Munich, Bavaria, Germany.
authors.forename: Barbara
authors.initials: B
authors.lastname: Fellerhoff-Losch
authors.affiliation: Department of Neuroscience, Uppsala University, Uppsala, Sweden.
authors.forename: Sergiy V
authors.initials: SV
authors.lastname: Korol
authors.affiliation: Department of Infection, Immunity and Inflammation, Cochin Institute, CNRS UMR8104, INSERM U1016, Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
authors.forename: Yonatan
authors.initials: Y
authors.lastname: Ganor
authors.affiliation: Immunotherapy Research Center, Munich, Bavaria, Germany.
authors.forename: Songhai
authors.initials: S
authors.lastname: Gu
authors.affiliation: The Joseph Sagol Neuroscience Center, Haim Sheba Medical Center, Tel Hashomer, Israel.
authors.forename: Itzik
authors.initials: I
authors.lastname: Cooper
authors.affiliation: Veterinary Resources, The Weizmann Institute of Science, Rehovot, Israel.
authors.forename: Raya
authors.initials: R
authors.lastname: Eilam
authors.affiliation: Sheba Medical Center, The Ella Institute for Treatment and Research of Melanoma, Tel Hashomer, Israel.
authors.forename: Michal
authors.initials: M
authors.lastname: Besser
authors.affiliation: Pain Medicine Institute, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel.
authors.forename: Meidan
authors.initials: M
authors.lastname: Goldfinger
authors.affiliation: Department of Gastroenterology, Rambam Health Care Campus & Bruce Rappaport School of Medicine, Technion Institute of Technology, Haifa, Israel.
authors.forename: Yehuda
authors.initials: Y
authors.lastname: Chowers
authors.affiliation: Immunotherapy Research Center, Munich, Bavaria, Germany.
authors.forename: Rudolf
authors.initials: R
authors.lastname: Wank
authors.affiliation: Department of Neuroscience, Uppsala University, Uppsala, Sweden.
authors.forename: Bryndis
authors.initials: B
authors.lastname: Birnir
authors.affiliation: School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel. mial@ekmd.huji.ac.il.|Institute of Gene Therapy, Hadassah University Hospital, Jerusalem, Israel. mial@ekmd.huji.ac.il.|School of Behavioral Sciences, Academic College of Tel Aviv-Jaffa, Tel Aviv, Israel. mial@ekmd.huji.ac.il.
authors.forename: Mia
authors.initials: M
authors.lastname: Levite
mesh_terms: D000818:Animals; D001327:Autoimmune Diseases / Q000276:immunology / Q000378:metabolism; D015153:Blotting, Western; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism*; D024202:Electrophoretic Mobility Shift Assay; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D007249:Inflammation / Q000276:immunology / Q000378:metabolism; D051662:Kv1.1 Potassium Channel / Q000378:metabolism*; D008297:Male; D051379:Mice; D016513:Mice, SCID; D016328:NF-kappa B / Q000276:immunology / Q000378:metabolism; D018408:Patch-Clamp Techniques; D016133:Polymerase Chain Reaction; D015398:Signal Transduction / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
chemical_list: D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha; D051662:Kv1.1 Potassium Channel
keywords: Autoimmune diseases; Immunotherapy; Inflammation; Kv1.1; NFκB; Non-canonical pathway; Pro-inflammatory cytokines; T cells; TNFα; Voltage-gated potassium channels