Pregnancy represents a unique immunological situation. Though paternal antigens expressed by the conceptus are recognized by the immune system of the mother, the immune response does not harm the fetus. Progesterone and a progesterone induced protein; PIBF are important players in re-adjusting the functioning of the maternal immune system during pregnancy. PIBF expressed by peripheral pregnancy lymphocytes, and other cell types, participates in the feto-maternal communication, partly, by mediating the immunological actions of progesterone. Several splice variants of PIBF were identified with different physiological activity. The full length 90 kD PIBF protein plays a role in cell cycle regulation, while shorter splice variants are secreted and act as cytokines. Aberrant production of PIBF isoforms lead to the loss of immune-regulatory functions, resulting in and pregnancy failure. By up regulating Th2 type cytokine production and by down-regulating NK activity, PIBF contributes to the altered attitude of the maternal immune system. Normal pregnancy is characterized by a Th2-dominant cytokine balance, which is partly due to the action of the smaller PIBF isoforms. These bind to a novel form of the IL-4 receptor, and induce increased production of IL-3, IL-4, and IL-10. The communication between the conceptus and the mother is established via extracellular vesicles (EVs). Pre-implantation embryos produce EVs both in vitro, and in vivo. PIBF transported by the EVs from the embryo to maternal lymphocytes induces increased IL-10 production by the latter, this way contributing to the Th2 dominant immune responses described during pregnancy.