Dynamic Changes in the Phenotype of Dendritic Cells in the Uterus and Uterine Draining Lymph Nodes After Coitus

Abstract

Dendritic cells (DCs) are essential for successful embryo implantation. However, the properties of uterine DCs (uDCs) during the implantation period are not well characterized. In this study, we investigated the dynamic changes in the uDC phenotypes during the period between coitus and implantation. In virgin mice, we evaluated the expressions of CD103 and XCR1, this is the first report to demonstrate uDCs expressing CD103 in XCR1 + cDC1s and XCR1 + cDC2s. On day 0.5 post coitus (pc), the number of uterine CD11c + CD103 − MHC classII high CD86 high-mature DCs rapidly increased and then decreased to non-pregnancy levels on days 1.5 and 2.5 pc. On day 3.5 pc just before implantation, the number of CD11c + CD103 + MHC class II dim CD86 dim-immature DCs increased in the uterus. The increase in mature uDCs on day 1.5 pc was observed in both allogeneic-and syngeneic mating, suggesting that sexual intercourse, or semen, play a role in this process. Meanwhile, the increase in immature uDCs on day 3.5 pc was only observed in allogeneic mating, suggesting that allo-antigens in the semen contribute to this process. Next, to understand the turnover and migration of uDCs, we monitored DC movement in the uterus and uterine draining lymph nodes (dLNs) using photoconvertible protein Kikume Green Red (KikGR) mice. On day 0.5 pc, uDCs were composed of equal numbers of remaining DCs and migratory DCs. However, on day 3.5 pc, uDCs were primarily composed of migratory DCs, suggesting that most of the uDCs migrate from the periphery just before implantation. Finally, we studied the expression of PD-L2-which induces immunoregulation-on DCs. On day 3.5 pc, PD-L2 was expressed on CD103 +-mature and CD103 −-mature DCs in the uterus. However, PD-L2 expression on CD103 −immature DCs and CD103 +-immature DCs was very low. Furthermore, both remaining and migratory DCs in the uterus and uterus-derived-DCs in the dLNs on day 3.5 pc highly expressed PD-L2 on their surface. Therefore, our study findings provide a better understanding of the dynamic changes occurring in uterine DCs and dLNs in preparation for implantation following allogeneic-and syngeneic mating.

Molecules and Prostaglandins Related to Embryo Tolerance

“…PGE2 also plays a significant role in peri-implantation in a mouse uterus through the expression of EP2 and EP4 receptors, which increase cAMP levels during the implantation and decidualization processes. EP4 induces the activation of VEGF (growth factor vascular endothelial), increasing vascular permeability of the endometrium (146), implantation and decidualization, together with PGF2 (132). Inadequate production of prostaglandins in mice, and possibly in humans, may explain some cases of infertility (147).…”

Seminal Plasma and Seminal Plasma Exosomes of Aged Male Mice Affect Early Embryo Implantation via Immunomodulation

“…T cell-activating macrophages and DCs are recruited into uterine tissue in response to semen-induced cytokine and chemokine signals ( 33 ). An article published recently verified migration of uDCs from the periphery just before implantation ( 20 ). Their data also showed an increase of immature uDCs on day 3.5 pc, which support the concept that immature DCs may participate in embryo implantation via regulating fetal–maternal tolerance ( 34 ).…”

“…Tolerant DCs are more resistant to maturation upon various stimulations. Yasuda et al discovered that immature phenotype made up the main component of uterine DCs (uDCs) 3.5 days post coitum (dpc), indicating that immature DCs may play an important role in successful implantation (20) and demonstrating the influence of male SP on the female reproductive immune microenvironment.…”

Progress in the understanding of the pathophysiology of immunologic maladaptation related to early-onset preeclampsia and metabolic syndrome related to late-onset preeclampsia

“…38 Seminal plasma priming induces the increased number of immature DCs that induce tolerance in the uterus. 35,39,40 These immature type of DCs flows into the uterus from the lymph nodes or tissues other than the uterus and peaks 3.5 days after mating just before implantation in mice. 39 In contrast, the mature type of DCs moves into uterine draining lymph nodes and is thought to induce the development of PAS-Treg cells.…”