The voltage-gated Kv1.3 K+ channel in effector memory T cells as new target for MS
Heike Wulff, … , Christine Beeton, K. George Chandy
Heike Wulff, … , Christine Beeton, K. George Chandy
Published June 1, 2003
Citation Information: J Clin Invest. 2003;111(11):1703-1713. https://doi.org/10.1172/JCI16921.
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Article Autoimmunity

The voltage-gated Kv1.3 K+ channel in effector memory T cells as new target for MS

Abstract

Through a combination of fluorescence microscopy and patch-clamp analysis we have identified a striking alteration in K+ channel expression in terminally differentiated human CCR7–CD45RA– effector memory T lymphocytes (TEM). Following activation, TEM cells expressed significantly higher levels of the voltage-gated K+ channel Kv1.3 and lower levels of the calcium-activated K+ channel IKCa1 than naive and central memory T cells (TCM). Upon repeated in vitro antigenic stimulation, naive cells differentiated into Kv1.3highIKCa1low TEM cells, and the potent Kv1.3-blocking sea anemone Stichodactyla helianthus peptide (ShK) suppressed proliferation of TEM cells without affecting naive or TCM lymphocytes. Thus, the Kv1.3highIKCa1low phenotype is a functional marker of activated TEM lymphocytes. Activated myelin-reactive T cells from patients with MS exhibited the Kv1.3highIKCa1low TEM phenotype, suggesting that they have undergone repeated stimulation during the course of disease; these cells may contribute to disease pathogenesis due to their ability to home to inflamed tissues and exhibit immediate effector function. The Kv1.3highIKCa1low phenotype was not seen in glutamic acid decarboxylase, insulin-peptide or ovalbumin-specific and mitogen-activated T cells from MS patients, or in myelin-specific T cells from healthy controls. Selective targeting of Kv1.3 in TEM cells may therefore hold therapeutic promise for MS and other T cell–mediated autoimmune diseases.

Authors

Heike Wulff, Peter A. Calabresi, Rameeza Allie, Sung Yun, Michael Pennington, Christine Beeton, K. George Chandy

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Figure 1

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Myelin antigen–activated T cells from MS patients express the distinctiv...
Myelin antigen–activated T cells from MS patients express the distinctive Kv1.3highIKCa1lowphenotype. (a) Kv1.3 and IKCa1 currents in TCLs from MS patients and controls measured 48 hours after activation with MBP. The numbers 1, 2, and 3 in the Kv1.3 traces represent traces after the first, second, and third depolarizing 200-ms pulse; the pulse interval is 1 second. (b) Kv1.3 channel number/cell in myelin antigen–activated TCLs (left) or mitogen-activated T cells (right) from MS patients or controls. Each data point constitutes the mean ± SEM of 20–30 cells from two to seven independent TCLs. Myelin antigens used were MBP (filled and open squares), MOG (filled and open triangles), and PLP (filled diamonds). Filled symbols, MSpatients; open symbols, control subjects. Mitogens used were soluble anti-CD3 mAb (50 ng/ml) and PMA (10 nM) plus ionomycin (175 nM) (data for both mitogens are grouped together). Filled circles, MS patients; open circles, controls. (c) Kv1.3 channel number/cell in MS patient T cells activated for 48 hours with the control antigens GAD65, insulin peptide, and ovalbumin. Due to the paucity of cells in these TCLs, IKCa1 expression was measured in only two to three cells per TCL.