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¹ Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104
² Institute für Neurophysiologie, University of Cologne, Cologne D-50931, Germany
³ Department of Safety Assessment, GlaxoSmithKline, King of Prussia, PA 19406
⁴ Department of Medicine, School of Medicine, University of Pennsylvania, Philadelphia, PA 19104
⁵ Department of Biomedical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY 14853
⁶ Department of Immunology, Nagasaki University, School of Medicine, Nagasaki, 852-8523, Japan

Address correspondence to Bruce D. Freedman, Dept. of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, 3800 Spruce Street, Philadelphia, PA 19104. Phone: 215-573-8218; Fax: 215-898-0719; E-mail: bruce{at}vet.upenn.edu

Ionic signaling pathways, including voltage-dependent potassium (Kv) channels, are instrumental in antigen-mediated responses of peripheral T cells. However, how Kv channels cooperate with other signaling pathways involved in T cell activation and differentiation is unknown. We report that multiple Kv channels are expressed by naive CD4⁺ lymphocytes, and that the current amplitude and kinetics are modulated by antigen receptor–mediated stimulation and costimulatory signals. Currents expressed in naive CD4⁺ lymphocytes are consistent with Kv1.1, Kv1.2, Kv1.3, and Kv1.6. Effector CD4⁺ cells generated by optimal TCR and costimulation exhibit only Kv1.3 current, but at approximately sixfold higher levels than naive cells. CD4⁺ lymphocytes anergized through partial stimulation exhibit similar Kv1.1, Kv1.2, and/or Kv1.6 currents, but approximately threefold more Kv1.3 current than naive cells. To determine if Kv channels contribute to the distinct functions of naive, effector, and anergized T cells, we tested their role in immunoregulatory cytokine production. Each Kv channel is required for maximal IL-2 production by naive CD4⁺ lymphocytes, whereas none appears to play a role in IL-2, IL-4, or IFN- production by effector cells. Interestingly, Kv channels in anergized lymphocytes actively suppress IL-4 production, and these functions are consistent with a role in regulating the membrane potential and calcium signaling.

Key Words: potassium channel • CD28 • patch clamp • superantigen • anergy

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