Introduction
A pregnant mother faces a potential quandary, as her growing fetus is semiallogeneic, but her immune system has to recognize the developing child as 'self' in order to not reject it. Thus, a well-orchestrated adaptation of the maternal immune system to the fetus is required to ensure a successful pregnancy. Recent studies have characterized a unique population of immune cells, the decidual NK (dNK) cells, as identified by their CD56high CD16- phenotype, that are involved in this adaptation1. These dNK cells comprise the largest population of immune cells during the first trimester of pregnancy in humans and can be found in close apposition to invasive trophoblast cells2—the cells derived from the fertilized egg that mediate implantation of the embryo into the mother's womb. Understanding the in vivo function of this distinct NK population, especially with regard to the suppression of immune rejection via the maternal immune system, poses a major challenge to not only reproductive immunologists but all immunologists.
Repression of dNK cytotoxicity toward fetal cells via NK receptor inhibitory pathways was initially thought to be the key mechanism by which induction of fetomaternal immune tolerance was maintained. However, this notion has recently been challenged as overly simplistic. On the basis of pioneering work by Anne Croy's group, it is now evident that depletion of NK cells in mice results in an altered vascular remodeling rather than in fetal loss2, 3. In contrast, decidual and systemic regulatory T (Treg) cells are known to induce tolerance toward fetal antigens, and—unlike the case with NK cells—the depletion of these cells leads to fetal loss4, 5. Hanna et al.1 have now shown that human dNK cells control trophoblast invasion and vascular remodeling through their ability to secrete an array of angiogenesis-regulating molecules, both chemokines and cytokines, such as vascular endothelial growth factor, placental growth factor and interleukin-8 (IL-8). Thus, a new paradigm of dNK cell function has emerged in which, beyond simply killing cells, they also promote the regulation of tissue homeostasis.
But cell communication in the decidua is a two-way street. In addition to maternal uterine cells controlling trophoblast invasion, invasive trophoblast cells can also regulate migration of immune cell populations such as CD56+ NK cells into the decidua via secretion of chemokines such as stromal cell-derived factor-1 (SCDF) and macrophage inflammatory protein-1
(ref. 6). The clinical relevance of this bidirectional communication is reinforced by a recent gene linkage analysis by Hiby et al7. This group followed up on the prediction that recognition of polymorphic human leukocyte antigen C (HLA-C) molecules on trophoblast cells by dNK cells via killer immunoglobulin receptors (KIRs) is a key factor in the development of preeclampsia. They observed that a distinct combination of an activating KIR variant (AA genotype) on peripheral maternal NK cells and fetal HLA-C2 expression—both of which are inherited—is associated with an increased risk for preeclampsia. This finding suggests that the NK receptor–ligand interaction in this scenario may only engage the inhibitory KIR2DL1 receptor, which in turn results in too much inhibition of dNK cells and poor trophoblast invasion into the uterine arteries. Hence, favoring dNK activation, as seen in other combinations of KIR variants and fetal HLA-C, is protective against preeclampsia by supplying sufficient amounts of NK-derived growth factors and chemokines, in turn promoting trophoblast invasion and vascular remodeling (please see the related News & Views on pages 1187–1188 regarding the role of angiogenesis and preeclampsia).
It remains to be validated that dNK cell phenotypes mirror the observation made by Hiby et al.7, given that in the context of preeclampsia, they analyzed the NK cell genotypes in peripheral blood cells rather than in cells from the decidua. However, a similar finding in decidual cells seems likely, as evolutionary selection against this combination is observed in various human populations, revealed by a reciprocal relationship between the activating KIR variant and HLA-C2 frequencies. Likewise, similar to the study by Hiby et al.7, favorable or unfavorable coinheritance of HLA ligand–NK receptor heterogeneity are observed in various other pathological conditions, such as the inefficiency of clearing viral infections, the susceptibility to malignancies or the risk of developing autoimmune diseases, such as type I diabetes8.
Although such NK cell licensing via HLA alleles provides a rationale for interindividual differences in NK cell potency associated with susceptibility to certain diseases, the pivotal potential of NK cells to be educated in the context of immune surveillance during pregnancy should not be overlooked. Evidence published over the past decade reveals an interaction between NK cells and dendritic cells (DCs), which is commonly referred to as an immunostimulatory synapse. Research helping us to understand mechanisms involved in DC-mediated NK cell education are also strongly addressed in the context of reproduction—fostered not only by the observation of spatial adjacencies of both cell subsets in murine and human decidua9, 10 but also by a wealth of published evidence on NK-DC cross talk in other settings of immunosurveillance. One recent example is the generation and education of tumor-rejecting and interferon-
(IFN-)-producing NK cells, which can be induced in mice upon stimulation with adoptively transferred DCs11. Immature DCs (iDCs), which are predominately present in the decidua of normally progressing human and murine pregnancies5, 9, are known to induce NK cell activation12. As shown in mice, iDCs also promote expansion of Treg cells, which mediate protection of the fetus5. Treg cells target the NK-activating receptor NKG2D to inhibit several NK cell functions, including proliferation, cytokine production, cytolytic activity and tumor rejection12, suggesting that dNK may also receive educational signals from DCs via Treg cells.
Reciprocally, NK cells can influence the activation and maturation of DCs, resulting in DC maturation or lysis through, for example, the NKp30 receptor13. An important feature of the NK cell education is mediated via IL-18, which induces IFN- secretion from NK cells, which in turn leads to IL-12p70 secretion by DCs, subsequently resulting in T helper 1 polarization14. Moreover, a direct regulation of T cell adaptive immune responses by NK cells has also been shown. For example, enhanced CD4 and CD8 T cell proliferation is dependent on T cell surface ligand (CD28 and OX40) binding to co-stimulatory receptors (CD80, CD86 and NK2B4) expressed by stimulated human NK cells15. Likewise, activated human NK cells express major histocompatibility complex (MHC) class II—akin to mature DCs—and, thus, can also present antigens directly to T cells, as shown in in vitro studies15.
Aside from cell-cell contact or cytokine stimulation operational in NK-DC cross talk, dNK cells may also be educated by hormones such as progesterone or estrogens, although it is yet to be fully resolved whether or not dNK cells express receptors for progesterone2, 15, 16. Although not mutually exclusive from a direct effect of progesterone on NK cells, an alternate education of NK cells via progesterone-regulated DCs can be proposed on the basis of the observations that DCs produce a growth factor essential for NK cell education, IL-15 (refs. 1,12,15,16). Thus, it may be speculated that progesterone promotes pregnancy maintenance either directly via NK cell education or indirectly via DCs.
Galectin-1 (Gal-1) has been shown to induce expansion and recruitment of tolerogenic DCs in mice synergistically with progesterone, thereby preventing fetal loss5. Interestingly, human uterine NK cells are capable of secreting large amounts of Gal-1 (ref. 17). Thus, Gal-1 may act as a global modulator of DCs as well as of NK cells toward induction of pregnancy maintenance.
New and exciting developments toward understanding NK cell licensing and education are now available, indicating that NK cells hold a central switchboard position when vascular remodeling and immune surveillance is needed (Fig. 1). This emerging evidence allows one to envision that NK cells may be educated toward a targeted and desired outcome—for example, by therapeutic approaches aiming for NK cell activation via DC-dependent pathways. Such an approach may avoid the severe side-effects seen upon systemic cytokine administration and may also be beneficial not only in the context of impaired pregnancy maintenance (for example, in preeclampsia or miscarriages) but also under other pathologic circumstances, such as infectious diseases, autoimmunity and malignancies.
Figure 1: A schematic diagram illustrating decidual NK cells as switchboards, licensed and educated to control trophoblast invasion and vascular remodeling and to interact with dendritic cells within the framework of an 'immunostimulatory synapse'.
BV, blood vessel; CCL, CC chemokine ligand; ICAM, intercellular adhesion molecule; MIP-1, macrophage inflammatory protein-1; MIC, MHC class I–related chain; mDC, mature DC; PlGF; placental growth factor; SIGN, specific ICAM-3–grabbing nonintegrin; SCDF-1, stromal cell-derived factor-1; TH1, T helper type 1; TNF-, tumor necrosis factor-; VEGF, vascular endothelial growth factor. The dotted arrow indicates possible activation. NKG2D, natural killer cell group 2 subfamily of the killer cell C-type lectin receptor; NK2B4, natural killer cell receptor 2B4, also known as CD244.
Kim Caesar
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