The voltage-gated Kv1.3 K(+) channel in effector memory T cells as new target for MS.
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 (T(EM)). Following activation, T(EM) 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 (T(CM)). Upon repeated in vitro antigenic stimulation, naive cells differentiated into Kv1.3(high)IKCa1(low) T(EM) cells, and the potent Kv1.3-blocking sea anemone Stichodactyla helianthus peptide (ShK) suppressed proliferation of T(EM) cells without affecting naive or T(CM) lymphocytes. Thus, the Kv1.3(high)IKCa1(low) phenotype is a functional marker of activated T(EM) lymphocytes. Activated myelin-reactive T cells from patients with MS exhibited the Kv1.3(high)IKCa1(low) T(EM) 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 Kv1.3(high)IKCa1(low) 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 T(EM) cells may therefore hold therapeutic promise for MS and other T cell-mediated autoimmune diseases.
Wulff
Heike
H
Department of Physiology and Biophysics, University of California Irvine, College of Medicine, Irvine, California 92697, USA.
Calabresi
Peter A
PA
Allie
Rameeza
R
Yun
Sung
S
Pennington
Michael
M
Beeton
Christine
C
Chandy
K George
KG
D000328:Adult; D000818:Animals; D017252:CD3 Complex / Q000096:biosynthesis; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D002118:Calcium / Q000378:metabolism; D002455:Cell Division; D002469:Cell Separation; D003063:Cnidaria / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004594:Electrophysiology; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D007156:Immunologic Memory; D051660:Intermediate-Conductance Calcium-Activated Potassium Channels; D051664:Kv1.3 Potassium Channel; D008297:Male; D008856:Microscopy, Fluorescence; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000276:immunology* / Q000628:therapy*; D010455:Peptides / Q000737:chemistry; D010641:Phenotype; D015221:Potassium Channels / Q000378:metabolism*; D024642:Potassium Channels, Voltage-Gated; D013601:T-Lymphocytes / Q000378:metabolism*
D017252:CD3 Complex; D051660:Intermediate-Conductance Calcium-Activated Potassium Channels; C496973:KCNA3 protein, human; C496923:KCNN4 protein, human; D051664:Kv1.3 Potassium Channel; D010455:Peptides; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated; D002118:Calcium