title: Functional blockade of the voltage-gated potassium channel Kv1.3 mediates reversion of T effector to central memory lymphocytes through SMAD3/p21cip1 signaling.
abstract: The maintenance of T cell memory is critical for the development of rapid recall responses to pathogens, but may also have the undesired side effect of clonal expansion of T effector memory (T(EM)) cells in chronic autoimmune diseases. The mechanisms by which lineage differentiation of T cells is controlled have been investigated, but are not completely understood. Our previous work demonstrated a role of the voltage-gated potassium channel Kv1.3 in effector T cell function in autoimmune disease. In the present study, we have identified a mechanism by which Kv1.3 regulates the conversion of T central memory cells (T(CM)) into T(EM). Using a lentiviral-dominant negative approach, we show that loss of function of Kv1.3 mediates reversion of T(EM) into T(CM), via a delay in cell cycle progression at the G2/M stage. The inhibition of Kv1.3 signaling caused an up-regulation of SMAD3 phosphorylation and induction of nuclear p21(cip1) with resulting suppression of Cdk1 and cyclin B1. These data highlight a novel role for Kv1.3 in T cell differentiation and memory responses, and provide further support for the therapeutic potential of Kv1.3 specific channel blockers in T(EM)-mediated autoimmune diseases.
authors: Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA.
authors: Lina
authors: L
authors: Hu
authors: Anne R
authors: AR
authors: Gocke
authors: Edward
authors: E
authors: Knapp
authors: Jason M
authors: JM
authors: Rosenzweig
authors: Inna V
authors: IV
authors: Grishkan
authors: Emily G
authors: EG
authors: Baxi
authors: Hao
authors: H
authors: Zhang
authors: Joseph B
authors: JB
authors: Margolick
authors: Katharine A
authors: KA
authors: Whartenby
authors: Peter A
authors: PA
authors: Calabresi
mesh_terms: D001327:Autoimmune Diseases / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D016203:CDC2 Protein Kinase / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D059447:Cell Cycle Checkpoints / Q000235:genetics / Q000276:immunology; D002455:Cell Division / Q000235:genetics / Q000276:immunology; D002478:Cells, Cultured; D056744:Cyclin B1 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D016195:G2 Phase / Q000235:genetics / Q000276:immunology; D006801:Humans; D007156:Immunologic Memory; D051664:Kv1.3 Potassium Channel / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D010766:Phosphorylation / Q000235:genetics / Q000276:immunology; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D051900:Smad3 Protein / Q000235:genetics / Q000276:immunology* / Q000378:metabolism
chemical_list: C534699:CCNB1 protein, human; C493956:CDKN1A protein, human; D056744:Cyclin B1; D050759:Cyclin-Dependent Kinase Inhibitor p21; D051664:Kv1.3 Potassium Channel; C497790:SMAD3 protein, human; D051900:Smad3 Protein; D016203:CDC2 Protein Kinase