Fifty per cent of fetal antigens are of paternal origin. There is ample evidence now that pregnancy is recognized by the maternal immune system; furthermore, the immune system reacts in a differential way resulting in successful or failed pregnancy. Due to chronic allogeneic stimulation by fetally derived antigens lymphocytes of pregnant women develop progesterone receptors (PRs). Lymphocyte PR expression is related to lymphocyte activation, independently from the hormonal environment. The percentage of PR positive lymphocytes increases throughout gestation. Recurrent abortion, spontaneous abortion, pre-term labour as well as term labour are associated with a decreased number of PR positive cells. If a sufficient concentration of progesterone is available, PR positive lymphocytes produce a 34 kDa protein, named the Progesterone Induced Blocking Factor (PIBF). PIBF affects various phases of the immune response, inhibits the release of arachidonic acid and exerts an anti-abortive effect in mice. PIBF signals via the Jak/STAT pathway, which results in a Th2 dominant cytokine pattern. The cytokine effects of PIBF are significantly reduced in STAT6 deficient cells. PIBF activates STAT6 and inhibits the phosphorylation of STAT4. Activation of the STAT6 pathway depends on ligation of the IL-4 receptor, thus it seems plausible that the IL-4R is involved in PIBF-induced STAT6 activation. Though PIBF does not bind to IL-4R, blocking of the latter abolishes PIBF-induced STAT6 activation, whereas blocking of the IL-13 receptor has no effect. Furthermore, PIBF fails to signal in IL-4R knock down cells. The requirement of the IL-4R for PIBF signaling could be due to the lack of intracellular domains in the PIBF receptor, therefore the possibility of the PIBF receptor being a GPI anchored protein was considered. Digesting the GPI-anchor with Phosphatidylinositol-specific Phospholipase C (PI-PLC) abolished the STAT6 activating effect of PIBF, while that of IL-4 remained intact. These data suggest the existence of a novel type of IL-4R, composed of the IL-4R and the GPI-anchored PIBF receptor. Upon ligation the GPI-anchored PIBF receptor combines with the alpha chain of the IL-4 receptor, and induces Jak1 phosphorylation, which in turn activates STAT6. In urine samples from healthy pregnant women PIBF concentrations continuously increase up to the 37th week of gestation and start to decline thereafter, to fall to a minimum value during labour. PIBF concentrations in urine of healthy pregnant women are significantly higher than in those of non-pregnant individuals or women at risk for premature pregnancy termination. In vitro data suggest a correlation between the rate of progesterone receptor expression as well as PIBF production and the success or failure of pregnancy, but provide no direct evidence for their role in maintaining gestation. To test the biological significance of our findings, we used animal systems. In vivo studies revealed that: a) The anti-abortive effect of the PIBF in vivo is manifested via inducing a Th2 dominant cytokine pattern and keeping the NK activity at a low level: b) A proper stimulation of the maternal immune system is required for the operation of the progesterone-dependent immunomodulatory pathway: c) Neutralization of endogenous PIBF results in pregnancy termination. These data allow the conclusion that the operation of progesterone-dependent immunomodulation contributes to maintaining normal gestation.