The Role of Progesterone in Feto-Maternal Immunological Cross Talk

Abstract

This review aims to provide a brief historical overview of the feto-maternal immunological relationship, which profoundly influences the outcome of pregnancy. The initial question posed in the 1950s by Medawar [Symp Soc Exp Biol. 1953; 7: 320–338] was based on the assumption that the maternal immune system recognizes the fetus as an allograft. Indeed, based on the association between HLA-matching and spontaneous miscarriage, it became obvious that immunological recognition of pregnancy is required for a successful gestation. The restricted expression of polymorphic HLA antigens on the trophoblast, together with the presence of nonpolymorphic MHC products, excludes recognition by both T and NK cells of trophoblast-presented antigens; however, γδ T cells, which constitute the majority of decidual T cells, are likely candidates. Indeed, a high number of activated, progesterone receptor-expressing γδ T cells are present in the peripheral blood of healthy pregnant women and, in the presence of progesterone, these cells secrete an immunomodulatory protein called progesterone-induced blocking factor (PIBF). As early as in the peri-implantation period, the embryo communicates with the maternal immune system via PIBF containing extracellular vesicles. PIBF contributes to the dominance of Th2-type reactivity which characterizes normal pregnancy by inducing increased production of Th2 cytokines. The high expression of this molecule in the decidua might be one of the reasons for the low cytotoxic activity of decidual NK cells.

Embryonic extracellular vesicles as informers to the immune cells at the maternal–fetal interface

“…As early as in the peri-implantation period, the embryo communicates with the endometrium releasing factors able to modulate these decidual immune cells [22,23]. Among these, soluble HLA-G, found in the embryonic secretome [24,25] is believed to represent a major player in the initiation of immunotolerance for the invading blastocyst into the decidual tissues.…”

“…Embryo-derived EVs have been also detected at the embryo-maternal interface in mouse implantation sites [23]. Pallinger and collaborators demonstrated that these EVs can transport progesterone-induced blocking factor (PIBF) [39].…”

“…The PIBF full-length form has been suggested to be able to modulate the invasiveness of both the trophoblast and malignant tumours [40,41] while the shorter form seems to act mainly by regulating NK cell activity. During normal pregnancy, decidual NK cells exert a low cytotoxic activity despite the abundant presence of cytotoxic molecules, such as perforin, in their cytoplasmic granules [23]. Interestingly, PIBF is thought to control this cytolytic effect by inhibiting degranulation and perforin liberation from NK cells [42].…”

Progesterone modulates the T‐cell response via glucocorticoid receptor‐dependent pathways

“…T reg cells not only suppress fetal rejection, 9 but also account for the amelioration of autoimmune diseases observed during pregnancy, such as rheumatoid arthritis, 10,11 autoimmune hepatitis, 12 and multiple sclerosis. [14][15][16][17][18][19] However, recent findings suggest that the conventional nuclear progesterone receptor (PR) might not be expressed or might be expressed at a very low level in T cells. [14][15][16][17][18][19] However, recent findings suggest that the conventional nuclear progesterone receptor (PR) might not be expressed or might be expressed at a very low level in T cells.…”

“…13 A direct action of progesterone on T cells has long been postulated. [14][15][16][17][18][19] However, recent findings suggest that the conventional nuclear progesterone receptor (PR) might not be expressed or might be expressed at a very low level in T cells. 3,13 These contradictory observations on PR expression need further clarification.…”