Characterization of the functional properties of the voltage-gated potassium channel Kv1.3 in human CD4+ T lymphocytes.
Previous studies have shown that central memory T (T(CM)) cells predominantly use the calcium-dependent potassium channel KCa3.1 during acute activation, whereas effector memory T (T(EM)) cells use the voltage-gated potassium channel Kv1.3. Because Kv1.3-specific pharmacological blockade selectively inhibited anti-CD3-mediated proliferation, whereas naive T cells and T(CM) cells escaped inhibition due to up-regulation of KCa3.1, this difference indicated a potential for selective targeting of the T(EM) population. We examined the effects of pharmacological Kv1.3 blockers and a dominant-negative Kv1.x construct on T cell subsets to assess the specific effects of Kv1.3 blockade. Our studies indicated both T(CM) and T(EM) CD4+ T cells stimulated with anti-CD3 were inhibited by charybdotoxin, which can block both KCa3.1 and Kv1.3, whereas margatoxin and Stichodactyla helianthus toxin, which are more selective Kv1.3 inhibitors, inhibited proliferation and IFN-gamma production only in the T(EM) subset. The addition of anti-CD28 enhanced proliferation of freshly isolated cells and rendered them refractory to S. helianthus, whereas chronically activated T(EM) cell lines appeared to be costimulation independent because Kv1.3 blockers effectively inhibited proliferation and IFN-gamma regardless of second signal. Transduction of CD4+ T cells with dominant-negative Kv1.x led to a higher expression of CCR7+ T(CM) phenotype and a corresponding depletion of T(EM). These data provide further support for Kv1.3 as a selective target of chronically activated T(EM) without compromising naive or T(CM) immune functions. Specific Kv1.3 blockers may be beneficial in autoimmune diseases such as multiple sclerosis in which T(EM) are found in the target organ.
Hu
Lina
L
Department of Neurology, Johns Hopkins School of Medicine, Baltimore, MD 21287, USA.
Pennington
Michael
M
Jiang
Qiong
Q
Whartenby
Katharine A
KA
Calabresi
Peter A
PA
D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D049109:Cell Proliferation / Q000187:drug effects; D002469:Cell Separation; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis / Q000378:metabolism; D006801:Humans; D007156:Immunologic Memory / Q000187:drug effects / Q000276:immunology; D051664:Kv1.3 Potassium Channel / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology; D026902:Potassium Channel Blockers / Q000494:pharmacology; D012680:Sensitivity and Specificity
D016207:Cytokines; D051664:Kv1.3 Potassium Channel; D026902:Potassium Channel Blockers