Role of endometrial immune cells in implantation

Abstract

Implantation of an embryo occurs during the mid-secretory phase of the menstrual cycle, known as the "implantation window." During this implantation period, there are significant morphologic and functional changes in the endometrium, which is followed by decidualization. Many immune cells, such as dendritic and natural killer (NK) cells, increase in number in this period and early pregnancy. Recent works have revealed that antigen-presenting cells (APCs) and NK cells are involved in vascular remodeling of spiral arteries in the decidua and lack of APCs leads to failure of pregnancy. Paternal and fetal antigens may play a role in the induction of immune tolerance during pregnancy. A balance between effectors (i.e., innate immunity and helper T [Th] 1 and Th17 immunity) and regulators (Th2 cells, regulatory T cells, etc.) is essential for establishment and maintenance of pregnancy. The highly complicated endocrine-immune network works in decidualization of the endometrium and at the fetomaternal interface. We will discuss the role of immune cells in the implantation period and during early pregnancy.

Keywords: Decidua; Dendritic Cells; Endometrium; Human; Implantation; Lymphocytes; Macrophages; Natural Killer Cells; Regulatory T Cells; Th17 Cells.

Figure 1

Role of dendritic cells (DCs) and macrophages in implantation. Ovarian steroid hormones, E2, and progesterone (P4) stimulate synthesis of growth factors from endometrial epithelial cells, including colony-stimulating factor (CSF-1) and leukemia inhibitor factor (LIF). Uterine DCs are required for efficient decidualization of the endometrium. Macrophages play a largely immune role at this stage (Modified from Pollard JW. J Clin Invest 2008;118:3832-5 [12]). TGF, transforming growth factor; sFLT, soluble FMS-like tyrosine kinase.

Figure 2

Proposed roles of uterine dendritic cells (DCs) in the regulation of angiogenesis and T cell action at the maternal-fetal interface. Monocytes are recruited to the uterus and differentiate into mature tolerogenic cells such as uDCs, under the influence of colony-stimulating factor (CSF-1), GM-CSF, and interleukin (IL)-4. Uterine DCs produce soluble FMS-like tyrosine kinase 1 (sFLT1) and transforming growth factor (TGF)-β1. sFLT1, a soluble form of VEGFR1, modulates the actions of vascular endothelial growth factor (VEGF), and TGF-β1 influences endothelial cell viability and suppresses cytotoxic CD8⁺ T cell function and development of regulatory T (Treg) cells ( Modified from Pollard JW. J Clin Invest 2008;118: 3832-5 [12]).

Figure 3

Molecular mechanisms associated with the two distinctive macrophage phenotypes in the deciduae. Mo, monocyte; TLR, toll-like receptor; iNOS, inducible NO synthase; NO, nitric oxide; IDO, indoleamine dioxygenase; COX2, cyclooxygenase 2; PGE₂, prostaglandin E₂; IL, interleukin; TNF, tumor necrosis factor (Modified from Nagamatsu T, et al. Am J Reprod Immunol 2010;63:460-71 [14]).

Figure 4

Possible mechanisms of the origin, expansion, migration, and function of Treg cells during pregnancy. APC, antigen presenting cells; TGF-β, transforming growth factor-β; IL, interleukin; LIF, leukemia inhibitor factor; HO-1, heme-oxygenase-1 (Modified from Leber A, et al. Am J Reprod Immunol 2010;63:445-59 [28]).

Figure 5

Number of NK cells in human endometrium or deciduae. The number of endometrial and decidual NK cells starts to increase in the mid-secretory phase and early pregnancy, reaches a peak at the end of the first trimester, and then decreases as the fetus approaches term (Modified from King A, et al. Dev Immunol 1991;1: 169-90 [39]).

Figure 6

Cell composition of the endometrium and decidua and the phenotype and functions of endometrial NK (eNK) and decidual NK (dNK) cells (Modified from Manaster I, et al. Placenta 2008;29 Suppl A:S60-6 [41]). NK, natural killer; NCR, natural cytotoxicity receptors; IFN, interferon; IL, interleukin.