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Review
. 2014 May;124(5):1872-9.
doi: 10.1172/JCI68107. Epub 2014 May 1.

Uterine NK cells: active regulators at the maternal-fetal interface

Ashley Moffett, Francesco Colucci
Review

Uterine NK cells: active regulators at the maternal-fetal interface

Ashley Moffett et al. J Clin Invest. 2014 May.

Abstract

Pregnancy presents an immunological conundrum because two genetically different individuals coexist. The maternal lymphocytes at the uterine maternal-fetal interface that can recognize mismatched placental cells are T cells and abundant distinctive uterine NK (uNK) cells. Multiple mechanisms exist that avoid damaging T cell responses to the fetus, whereas activation of uNK cells is probably physiological. Indeed, genetic epidemiological data suggest that the variability of NK cell receptors and their MHC ligands define pregnancy success; however, exactly how uNK cells function in normal and pathological pregnancy is still unclear, and any therapies aimed at suppressing NK cells must be viewed with caution. Allorecognition of fetal placental cells by uNK cells is emerging as the key maternal-fetal immune mechanism that regulates placentation.

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Figures

Figure 1
Figure 1. Maternal immune response to fetus and placenta.
The maternal immune system does not ignore the fetal allograft. Antibodies specific for paternally inherited Rhesus D antigen and for HLA molecules — or, rarely, T cells specific for mismatched minor histocompatibility antigens — are found in the maternal circulation. However, these T cells do not normally reach the fetus itself, as this is protected by several mechanisms, including the placental barrier. The uterine mucosa is in direct contact with the fetal placenta at the maternal-fetal interface. This is the major site where fetal placental cells (not the embryo proper) are directly in contact with maternal tissues. The decidua is a specialized tissue that is rich in uNK and myeloid cells and also contains maternal T cells, including effector T cells and Tregs. Although it appears clear that uNK cells have receptors that can interact with HLA-C molecules on invasive trophoblast cells at the interface, how effector T cells might interact with the trophoblast cells is unclear. Circulating in the maternal blood are antifetal antibodies and T cells together with fetal cells and trophoblast cells.
Figure 2
Figure 2. NK cell education and recognition of allogeneic paternal MHC molecules on trophoblast cells.
Individuals inherit one KIR haplotype on chromosome 19 from each parent. Each haplotype contains 7–15 genes (only a few are depicted here for clarity). During NK cell differentiation, KIR genes are expressed in developing NK cells. Each NK cell expresses 0–5 KIRs. Some of the KIRs bind to self MHC molecules and educate NK cells to be tolerant of self and also to react to the absence of self. Allogeneic, paternal MHC molecules on the trophoblast cell can interact with some KIRs on the uNK cell; however, it is not known whether this new interaction educates uNK cells or if the uNK cells recognize the paternal, allogeneic MHC molecule as foreign, generating an alloresponse.
Figure 3
Figure 3. Haploidentical bone marrow transplantation has parallels with maternal allorecognition.
Children inherit one MHC haplotype from each parent. In haploidentical bone marrow transplantation, T cell–depleted donor cells from one parent are transferred to a recipient child. In this example, the recipient child has leukemia, the mother is the donor, and her NK cells express a set of KIRs (blue) that bind and are inhibited by MHC molecules on the child’s leukemic cells. Other donor uNK cells expressing KIRs (yellow) that do not bind the child’s MHC molecules are not inhibited and will destroy the cancer cells. A third group of donor NK cells expresses activating KIRs (green), which, upon binding to the child’s MHC molecules, are activated to destroy leukemic cells. In the latter two situations, donor NK cells also destroy the patient’s normal hematopoietic cells, including the APCs, and this contributes to preventing graft-versus-host disease caused by residual donor maternal T cells. These three types of interactions are equivalent to the situation between KIRs expressed by maternal uNK cells (donor) and MHC molecules on fetal trophoblast cells (recipient).
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