Uterine MHC Class I Molecules and β2-Microglobulin Are Regulated by Progesterone and Conceptus Interferons during Pig Pregnancy

Abstract

MHC class I molecules and β2-microglobulin (β2m) are membrane glycoproteins that present peptide Ags to TCRs, and bind to inhibitory and activating receptors on NK cells and other leukocytes. They are involved in the discrimination of self from non-self. Modification of these molecules in the placenta benefits pregnancy, but little is known about their genes in the uterus. We examined the classical class I swine leukocyte Ags (SLA) genes SLA-1, SLA-2, and SLA-3, the nonclassical SLA-6, SLA-7, and SLA-8 genes, and the β2m gene in pig uterus during pregnancy. Uterine SLA and β2m increased in luminal epithelium between days 5 and 9, then decreased between days 15 and 20. By day 15 of pregnancy, SLA and β2m increased in stroma and remained detectable through day 40. To determine effects of estrogens, which are secreted by conceptuses to prevent corpus luteum regression, nonpregnant pigs were treated with estradiol benzoate, which did not affect the SLA or β2m genes. In contrast, progesterone, which is secreted by corpora lutea, increased SLA and β2m in luminal epithelium, whereas a progesterone receptor antagonist (ZK137,316) ablated this up-regulation. To determine effects of conceptus secretory proteins (CSP) containing IFN-δ and IFN-γ, nonpregnant pigs were implanted with mini-osmotic pumps that delivered CSP to uterine horns. CSP increased SLA and β2m in stroma. Cell-type specific regulation of SLA and β2m genes by progesterone and IFNs suggests that placental secretions control expression of immune regulatory molecules on uterine cells to provide an immunologically favorable environment for survival of the fetal-placental semiallograft.

Comparative aspects of implantation

“…In contrast, major histocompatibility complex class I molecules and b2-microglobulin that regulate immune rejection responses are silenced in LE/sGE, perhaps to protect the conceptus allograft. Similar results have been reported for pigs (Joyce et al 2008). Details on the regulation of expression and potential functions of LGALS15, cathepsin L, cystatin C, WNT7A, HIF1A, HIF2A, GRP, IGF2, MHC class I molecules, and b2-microglobulin have been reported recently (see Spencer et al 2007).…”

Novel insights into the mechanisms of pregnancy establishment: regulation of prostaglandin synthesis and signaling in the pig

“…IFND and IFNG exert an effect in the endometrium by cooperative induction of cytokinespecific transcription factors, such as STAT1 (Joyce et al 2007). Interferon response genes, swine leukocyte antigens (MHC class I molecules in pigs; SLA) class I and b 2 microglobulin (B2M), which are involved in the discrimination of self from non-self by the immune system, are cell type-specifically regulated in the endometrium (Joyce et al 2008). Downregulation of SLA class I and B2M expression in uterine LE and lack of expression of these genes in trophoblast (Ramsoondar et al 1999), may be important for preventing fetal allograft rejection.…”

Identification of differentially expressed genes in the oviduct of two rabbit lines divergently selected for uterine capacity using suppression subtractive hybridization

“…It is well accepted that MHC class I molecules and B2M are involved in discrimination of self from non-self during pregnancy and a down-regulation of their expression is beneficial to prevent fetus rejection (Ramsoondar et al 1999;Joyce et al 2008). A higher expression of this gene may be related with the reduction of embryo survival observed in the rabbits of the L line; however, further investigation is required to verify this hypothesis.…”