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Characterization of the Functional Properties of the Voltage-Gated Potassium Channel Kv1.3 in Human CD4⁺ T Lymphocytes¹

Lina Hu^*, Michael Pennington, Qiong Jiang, Katharine A. Whartenby and Peter A. Calabresi^2,*

^* Department of Neurology and Sidney Kimmel Cancer Center, Johns Hopkins School of Medicine, Baltimore, MD 21287; and Bachem Bioscience, King of Prussia, PA 19406

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- 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- 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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by Grant NS041435 from the National Institutes of Health (to P.A.C.).

² Address correspondence and reprint requests to Dr. Peter A. Calabresi, Department of Neurology, Johns Hopkins Medical Institutions, 600 North Wolfe Street, Baltimore, MD 21287. E-mail address: pcalabr1{at}jhmi.edu

³ Abbreviations used in this paper: T_CM, central memory T; ChTx, charybdotoxin; DN, dominant negative; MBP, myelin basic protein; MgTx, margatoxin; MS, multiple sclerosis; ShK, Stichodactyla helianthus toxin; TCL, T cell line; T_EM, effector memory T.