A Nongenomic Mechanism for Progesterone-mediated Immunosuppression: Inhibition of K(+) Channels, Ca(2+) 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(+) channels (K(V) and K(Ca), respectively), resulting in depolarization of the membrane potential. As a result, Ca(2+) 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+) signals after thapsigargin stimulation, as well as oscillatory Ca(2+) signals, but not the Ca(2+) 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 Ca(2+) and Cl(−) channels. We propose that direct inhibition of K(+) channels in T cells by progesterone contributes to progesterone-induced immunosuppression.