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 G. Baxi, Hao Zhang, Joseph B. Margolick, Katharine A. Whartenby, Peter A. Calabresi

Research output: Contribution to journalArticlepeer-review

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

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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