Functional blockade of the voltage-gated potassium channel Kv1.3 mediates reversion of T effector to central memory lymphocytes through SMAD3/p21 cip1 signaling

Lina Hu, Anne R. Gocke, Edward Knapp, Jason M. Rosenzweig, Inna V. Grishkan, Emily Grace Baxi, Hao Zhang, Joseph Bernard Margolick, Katharine Whartenby, Peter Calabresi

Research output: Contribution to journalArticle

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 EMinto 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.

Original languageEnglish (US)
Pages (from-to)1261-1268
Number of pages8
JournalJournal of Biological Chemistry
Volume287
Issue number2
DOIs
StatePublished - Jan 6 2012

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Voltage-Gated Potassium Channels
Lymphocytes
Autoimmune Diseases
T-cells
T-Lymphocytes
Data storage equipment
Cyclin B1
Cell Differentiation
Cell Cycle
Chronic Disease
Up-Regulation
Maintenance
Phosphorylation
Pathogens
Cells

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this

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title = "Functional blockade of the voltage-gated potassium channel Kv1.3 mediates reversion of T effector to central memory lymphocytes through SMAD3/p21 cip1 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 EMinto 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.",
author = "Lina Hu and Gocke, {Anne R.} and Edward Knapp and Rosenzweig, {Jason M.} and Grishkan, {Inna V.} and Baxi, {Emily Grace} and Hao Zhang and Margolick, {Joseph Bernard} and Katharine Whartenby and Peter Calabresi",
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T1 - Functional blockade of the voltage-gated potassium channel Kv1.3 mediates reversion of T effector to central memory lymphocytes through SMAD3/p21 cip1 signaling

AU - Hu, Lina

AU - Gocke, Anne R.

AU - Knapp, Edward

AU - Rosenzweig, Jason M.

AU - Grishkan, Inna V.

AU - Baxi, Emily Grace

AU - Zhang, Hao

AU - Margolick, Joseph Bernard

AU - Whartenby, Katharine

AU - Calabresi, Peter

PY - 2012/1/6

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N2 - 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 EMinto 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.

AB - 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 EMinto 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.

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