title: Immunosuppressive evidence of Tityus serrulatus toxins Ts6 and Ts15: insights of a novel K(+) channel pattern in T cells.
abstract: The voltage-gated potassium channel Kv1.3 is a novel target for immunomodulation of autoreactive effector memory T cells, which play a major role in the pathogenesis of autoimmune diseases. In this study, the Ts6 and Ts15 toxins isolated from Tityus serrulatus (Ts) were investigated for their immunosuppressant roles on CD4(+) cell subsets: naive, effector (TEF ), central memory (TCM) and effector memory (TEM). The electrophysiological assays confirmed that both toxins were able to block Kv1.3 channels. Interestingly, an extended Kv channel screening shows that Ts15 blocks Kv2.1 channels. Ts6 and Ts15 significantly inhibit the proliferation of TEM cells and interferon-γ production; however, Ts15 also inhibits other CD4(+) cell subsets (naive, TEF and TCM). Based on the Ts15 inhibitory effect of proliferation of all CD4(+) cell subsets, and based on its blocking effect on Kv2.1, we investigated the Kv2.1 expression in T cells. The assays showed that CD4(+) and CD8(+) cells express the Kv2.1 channels mainly extracellularly with TCM cells expressing the highest number of Kv2.1 channels. We also provide in vivo experimental evidence to the protective effect of Ts6 and Ts15 on delayed-type hypersensitivity reaction. Altogether, this study presents the immunosuppressive behaviour of Ts6 and Ts15 toxins, indicating that these toxins could be promising candidates for autoimmune disease therapy. Moreover, this is the first report illustrating the involvement of a novel K(+) channel subtype, Kv2.1, and its distribution in T-cell subsets.
authors.affiliation: Department of Physics and Chemistry, School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Ribeirão Preto, SP, Brazil.
authors.forename: Manuela B
authors.initials: MB
authors.lastname: Pucca
authors.affiliation: Department of Biochemistry and Immunology, School of Medicine of Ribeirão Preto, University of São Paulo, Ribeirão Preto, SP, Brazil.
authors.forename: Thaís B
authors.initials: TB
authors.lastname: Bertolini
authors.affiliation: Department of Physics and Chemistry, School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Ribeirão Preto, SP, Brazil.
authors.forename: Felipe A
authors.initials: FA
authors.lastname: Cerni
authors.affiliation: Department of Physics and Chemistry, School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Ribeirão Preto, SP, Brazil.
authors.forename: Karla C F
authors.initials: KC
authors.lastname: Bordon
authors.affiliation: Toxicology and Pharmacology, University of Leuven, Leuven, Belgium.
authors.forename: Steve
authors.initials: S
authors.lastname: Peigneur
authors.affiliation: Toxicology and Pharmacology, University of Leuven, Leuven, Belgium.
authors.forename: Jan
authors.initials: J
authors.lastname: Tytgat
authors.affiliation: Department of Biochemistry and Immunology, School of Medicine of Ribeirão Preto, University of São Paulo, Ribeirão Preto, SP, Brazil.
authors.forename: Vânia L
authors.initials: VL
authors.lastname: Bonato
authors.affiliation: Department of Physics and Chemistry, School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Ribeirão Preto, SP, Brazil.
authors.forename: Eliane C
authors.identifier: http://orcid.org/0000-0002-6712-6033
authors.initials: EC
authors.lastname: Arantes
mesh_terms: D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005260:Female; D006968:Hypersensitivity, Delayed / Q000276:immunology / Q000378:metabolism / Q000517:prevention & control; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D051664:Kv1.3 Potassium Channel / Q000037:antagonists & inhibitors / Q000378:metabolism; D008213:Lymphocyte Activation / Q000187:drug effects; D008297:Male; D008564:Membrane Potentials; D008807:Mice, Inbred BALB C; D026902:Potassium Channel Blockers / Q000494:pharmacology*; D024642:Potassium Channels, Voltage-Gated / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D012604:Scorpion Venoms / Q000494:pharmacology*; D012710:Serum Albumin, Bovine; D051669:Shab Potassium Channels / Q000037:antagonists & inhibitors / Q000378:metabolism; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D014982:Xenopus laevis
chemical_list: D007166:Immunosuppressive Agents; D051664:Kv1.3 Potassium Channel; D026902:Potassium Channel Blockers; D024642:Potassium Channels, Voltage-Gated; D012604:Scorpion Venoms; D051669:Shab Potassium Channels; C000607947:Ts15 toxin, Tityus serrulatus; C581454:Ts6 toxin, Tityus serrulatus; D012710:Serum Albumin, Bovine
keywords: Kv2.1; Tityus serrulatus; autoimmune diseases; memory T cell; scorpion