Uterine epithelial expression of the tumor necrosis factor superfamily: a strategy for immune privilege during pregnancy in a true epitheliochorial placentation species

Abstract

The maternal immune system tolerates semi-allogeneic placental tissues during pregnancy. Fas ligand (FASLG) and tumor necrosis factor superfamily 10 (TNFSF10) are known to be components of maternal immune tolerance in humans and mice. However, the role of FASLG and TNFSF10 in the tolerance process has not been studied in pigs, which form a true epitheliochorial type placenta. Thus, the present study examined the expression and function of FASLG and TNFSF10 and their receptors at the maternal-conceptus interface in pigs. The endometrium and conceptus tissues expressed FASLG and TNFSF10 and their receptor mRNAs during pregnancy in a stage-specific manner. During pregnancy, FASLG and TNFSF10 proteins were localized predominantly to endometrial luminal epithelial cells with strong signals on Day 30 to term and on Day 15, respectively, and receptors for TNFSF10 were localized to some stromal cells. Interferon-γ (IFNG) increased the expression of TNFSF10 and FAS in endometrial tissues. Co-culture of porcine endometrial epithelial cells over-expressing TNFSF10 with peripheral blood mononuclear cells yielded increased apoptotic cell death of lymphocytes and myeloid cells. In addition, many apoptotic T cells were found in the endometrium on Day 15 of pregnancy. The present study demonstrated that FASLG and TNFSF10 were expressed at the maternal-conceptus interface and conceptus-derived IFNG increased endometrial epithelial TNFSF10, which, in turn, induced apoptotic cell death of immune cells. These results suggest that endometrial epithelial FASLG and TNFSF10 may be critical for the formation of micro-environmental immune privilege at the maternal-conceptus interface for the establishment and maintenance of pregnancy in pigs.

Dynamic regulation of the transcriptome and proteome of the equine embryo during maternal recognition of pregnancy

“…The endometrial TNFSF10 could target the conceptus via uEVs. Based on the proposed functions in other species, this gene could also play a role in establishing an immune privileged environment at the maternal‐embryo interface in the mare 96 …”

Inhibitors of apoptosis: expression and regulation in the endometrium during the estrous cycle and at the maternal-conceptus interface during pregnancy in pigs

“…In non-primate species, menstruation does not occur as part of the estrous cycle, but apoptosis is nonetheless involved in endometrial remodeling during cyclical cell proliferation and degeneration. In mice, apoptosis in the uterine tissue is regulated by ovarian steroid hormones during the estrous cycle and occurs in the decidua after implantation [4][5][6] In pigs, apoptotic cells have been detected in the endometrium during the estrous cycle and pregnancy, mostly in the stroma at the time of implantation [7,8]. Our previous study in pigs showed that a large number of maternal T cells is recruited into the endometrium during the implantation period [9], and some T cells expressing cell death receptors undergo apoptosis [8].…”

Conceptus interferon gamma is essential for pregnancy maintenance in the pig

“…Pig conceptus interferons are not believed to have an antiluteolytic effect but rather paracrine effects which are suggested by the localization of their receptors on the maternal endometrium to regulate several ISG that aid in the complex communication between the maternal and fetal system (Johnson et al 2009). In one study, pig conceptus secretory proteins obtained from medium by culturing day 15 conceptuses for 30 hours were pooled and concentrated for intrauterine infusion and the results showed that these proteins had no antiluteolytic effect but they do, however, stimulate the secretion of PGE2 by uterine cells which is thought to enhance the structural integrity of the CL (Harney & Bazer 1989) Additionally, it has been reported that conceptus IFN are responsible for induction of endometrial FASLG, TNFSF10, and FAS expression on day 15 of pregnancy in the pig (Yoo et al 2020b). Furthermore, the same study showed that IFNG increases the expression of cysteine-X-cysteine chemokine ligands (CXCL) 9, 10, 11, and 12 which in turn, increase migration of T and NK cells, suggesting that IFN may play a role in recruitment of immune cells into the endometrium during the implantation period in pigs (Yoo et al 2020b).…”

“…In one study, pig conceptus secretory proteins obtained from medium by culturing day 15 conceptuses for 30 hours were pooled and concentrated for intrauterine infusion and the results showed that these proteins had no antiluteolytic effect but they do, however, stimulate the secretion of PGE2 by uterine cells which is thought to enhance the structural integrity of the CL (Harney & Bazer 1989) Additionally, it has been reported that conceptus IFN are responsible for induction of endometrial FASLG, TNFSF10, and FAS expression on day 15 of pregnancy in the pig (Yoo et al 2020b). Furthermore, the same study showed that IFNG increases the expression of cysteine-X-cysteine chemokine ligands (CXCL) 9, 10, 11, and 12 which in turn, increase migration of T and NK cells, suggesting that IFN may play a role in recruitment of immune cells into the endometrium during the implantation period in pigs (Yoo et al 2020b). While very little is known about conceptus interferons during early pregnancy in the pig, understanding their pathways could lead to more insight.…”

“…The loss of IFNG -/conceptuses is not only local, but there is an effect on the entire uterus as co-transfer with IFNG +/+ embryos resulted in pregnancy failure and all embryos recovered on day 30 were IFNG +/+ . Previous research investigated the possible role of IFNG in regulating maternal endometrial immunity during the implantation period in pigs by treating endometrial explants of cyclic animals with IFNG in vitro(Yoo et al 2020a;Yoo et al 2020b). Endometrial explants cultured with IFNG upregulated CIITA, IDO1, and TNFSF10 mRNA among several other IFNG-regulated genes and MHC class II molecules.…”