Hypoxia modulates early events in T cell receptor-mediated activation in human T lymphocytes via Kv1.3 channels

J Physiol. 2005 Apr 1;564(Pt 1):131-43. doi: 10.1113/jphysiol.2004.081893. Epub 2005 Jan 27.


T lymphocytes are exposed to hypoxia during their development and when they migrate to hypoxic pathological sites. Although it has been shown that hypoxia inhibits Kv1.3 channels and proliferation in human T cells, the mechanisms by which hypoxia regulates T cell activation are not fully understood. Herein we test the hypothesis that hypoxic inhibition of Kv1.3 channels induces membrane depolarization, thus modulating the increase in cytoplasmic Ca2+ that occurs during activation. Hypoxia causes membrane depolarization in human CD3+ T cells, as measured by fluorescence-activated cell sorting (FACS) with the voltage-sensitive dye DiBAC4(3). Similar depolarization is produced by the selective Kv1.3 channel blockers ShK-Dap22 and margatoxin. Furthermore, pre-exposure to such blockers prevents any further depolarization by hypoxia. Since membrane depolarization is unfavourable to the influx of Ca2+ through the CRAC channels (necessary to drive many events in T cell activation such as cytokine production and proliferation), the effect of hypoxia on T cell receptor-mediated increase in cytoplasmic Ca2+ was determined using fura-2. Hypoxia depresses the increase in Ca2+ induced by anti-CD3/CD28 antibodies in approximately 50% of lymphocytes. In the remaining cells, hypoxia either did not elicit any change or produced a small increase in cytoplasmic Ca2+. Similar effects were observed in resting and pre-activated CD3+ cells and were mimicked by ShK-Dap22. These effects appear to be mediated solely by Kv1.3 channels, as we find no influence of hypoxia on IKCa1 and CRAC channels. Our findings indicate that hypoxia modulates Ca2+ homeostasis in T cells via Kv1.3 channel inhibition and membrane depolarization.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Cell Hypoxia / physiology
  • Humans
  • Kv1.3 Potassium Channel
  • Lymphocyte Activation / physiology*
  • Membrane Potentials / physiology
  • Potassium Channels, Voltage-Gated / physiology*
  • Receptors, Antigen, T-Cell / physiology*
  • Signal Transduction / immunology
  • T-Lymphocytes / metabolism*
  • T-Lymphocytes / physiology
  • Time Factors


  • KCNA3 protein, human
  • Kv1.3 Potassium Channel
  • Potassium Channels, Voltage-Gated
  • Receptors, Antigen, T-Cell