A Nongenomic Mechanism for Progesterone-mediated Immunosuppression: Inhibition of K Ϩ Channels, Ca 2 Ϩ 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 ϩ channels (K V and K Ca , respectively), resulting in depolar-ization of the membrane potential. As a result, Ca 2 ϩ 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 ϩ signals after thapsigargin stimulation, as well as oscillatory Ca 2 ϩ signals, but not the Ca 2 ϩ transient after TCR stimulation. K ϩ 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 ϩ 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 ϩ channel, an inward rectifier K ϩ channel, or on lym-phocyte Ca 2 ϩ and Cl Ϫ channels. We propose that direct inhibition of K ϩ channels in T cells by progesterone contributes to progesterone-induced immunosuppression. Key words: T lymphocyte • K ϩ channel • calcium signaling • gene expression • nuclear factor of activated T cells I mmunosuppression within the uterus is crucial for the survival of the fetus (1, 2). Although the maternal immune system becomes sensitized to paternal antigens during pregnancy, fetal cells and placental trophoblasts bearing those antigens do not elicit a cytolytic immune response (3–5). High concentrations of progesterone in the placenta inhibit the maternal immune response against the fetal al-lograft (6, 7). The immunosuppressive effects of progester-one were demonstrated in vivo by prolonged survival of xe-nografts near silastic implants containing progesterone at concentrations typically found in the placenta (3, 6). In vitro assays have established that progesterone inhibits lympho-cyte activation and proliferation in response to allogeneic cells or mitogens (8–10). In contrast, progesterone does not inhibit the effector functions of previously activated cy-tolytic T cells (11). These data suggest that progesterone may interfere with the early phases of T cell activation. …