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From the Department of Physiology and Biophysics, University of California, Irvine, California 92697

The mechanism by which progesterone causes localized suppression of the immune response during pregnancy has remained elusive. Using human T lymphocytes and T cell lines, we show that progesterone, at concentrations found in the placenta, rapidly and reversibly blocks voltage-gated and calcium-activated K⁺ channels (K_V and K_Ca, respectively), resulting in depolarization of the membrane potential. As a result, Ca²⁺ signaling and nuclear factor of activated T cells (NF-AT)-driven gene expression are inhibited. Progesterone acts distally to the initial steps of T cell receptor (TCR)-mediated signal transduction, since it blocks sustained Ca²⁺ signals after thapsigargin stimulation, as well as oscillatory Ca²⁺ signals, but not the Ca²⁺ transient after TCR stimulation. K⁺ channel blockade by progesterone is specific; other steroid hormones had little or no effect, although the progesterone antagonist RU 486 also blocked K_V and K_Ca channels. Progesterone effectively blocked a broad spectrum of K⁺ channels, reducing both Kv1.3 and charybdotoxin–resistant components of K_V current and K_Ca current in T cells, as well as blocking several cloned K_V channels expressed in cell lines. Progesterone had little or no effect on a cloned voltage-gated Na⁺ channel, an inward rectifier K⁺ channel, or on lymphocyte Ca²⁺ and Cl^– channels. We propose that direct inhibition of K⁺ channels in T cells by progesterone contributes to progesterone-induced immunosuppression.

Key Words: T lymphocyte • K⁺ channel • calcium signaling • gene expression • nuclear factor of activated T cells

H.H. Kerschbaum's present address is Department of Physiology, Institute for Zoology, University of Salzburg, 5020 Salzburg, Austria. Claudia Eder's current address is Department of Neurophysiology, Institute of Physiology Humboldt University, D-10019 Berlin, Germany. P.A. Negulescu's present address is Aurora Biosciences, 11010 Torreyana Rd., San Diego, CA 92121.

G.R. Ehring and H.H. Kerschbaum contributed equally to this work.

Abbreviations used: [Ca²⁺]_i, intracellular free calcium concentration; CRAC, Ca²⁺ release–activated Ca²⁺; CTX, charybdotoxin; E_m, membrane potential; IP₃, inositol 1,4,5-trisphosphate; K_Ca, Ca²⁺-activated K⁺; K_V, voltage-gated K⁺; NF-AT, nuclear factor of activated T cells; TG, thapsigargin.

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