A Nongenomic Mechanism for Progesterone - mediated Immunosuppression : Inhibition of K 1 Channels , Ca 2 1 Signaling , and Gene Expression in T Lymphocytes

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 1 channels (K V and K Ca , respectively), resulting in depolarization of the membrane potential. As a result, Ca 2 1 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 Ca 2 1 signals after thapsigargin stimulation, as well as oscillatory Ca 2 1 signals, but not the Ca 2 1 transient after TCR stimulation. K 1 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 1 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 1 channel, an inward rectifier K 1 channel, or on lymphocyte Ca 2 1 and Cl 2 channels. We propose that direct inhibition of K 1 channels in T cells by progesterone contributes to progesterone-induced immunosuppression.