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.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Autoimmune Diseases / genetics
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Autoimmune Diseases / immunology
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Autoimmune Diseases / metabolism
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CD4-Positive T-Lymphocytes / immunology*
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CD4-Positive T-Lymphocytes / metabolism
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CDC2 Protein Kinase / genetics
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CDC2 Protein Kinase / immunology
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CDC2 Protein Kinase / metabolism
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Cell Cycle Checkpoints / genetics
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Cell Cycle Checkpoints / immunology
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Cell Division / genetics
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Cell Division / immunology
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Cells, Cultured
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Cyclin B1 / genetics
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Cyclin B1 / immunology
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Cyclin B1 / metabolism
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Cyclin-Dependent Kinase Inhibitor p21 / genetics
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Cyclin-Dependent Kinase Inhibitor p21 / immunology*
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Cyclin-Dependent Kinase Inhibitor p21 / metabolism
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G2 Phase / genetics
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G2 Phase / immunology
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Humans
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Immunologic Memory*
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Kv1.3 Potassium Channel / genetics
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Kv1.3 Potassium Channel / immunology*
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Kv1.3 Potassium Channel / metabolism
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Phosphorylation / genetics
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Phosphorylation / immunology
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Signal Transduction / genetics
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Signal Transduction / immunology*
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Smad3 Protein / genetics
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Smad3 Protein / immunology*
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Smad3 Protein / metabolism
Substances
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CCNB1 protein, human
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CDKN1A protein, human
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Cyclin B1
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Cyclin-Dependent Kinase Inhibitor p21
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Kv1.3 Potassium Channel
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SMAD3 protein, human
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Smad3 Protein
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CDC2 Protein Kinase