Understanding the role of killer cell immunoglobulin-like receptors in pregnancy complications

Abstract

Pregnancy is a unique immunological situation in which a fetus-bearing paternal histocompatibility antigens can survive in a maternal environment without apparent rejection. To face this challenge, cells of the uterine immune system show characteristic changes in absolute number and composition during pregnancy. Particularly relevant to this process are uterine natural killer (uNK) cells and their cell surface receptors, killer immunoglobulin-like receptors (KIRs). The main purpose of this review is to outline the current body of knowledge on the involvement of KIRs in the complications of pregnancy. Implantation depends on the invasion of embryonic trophoblast cells into maternal uterine tissue and remodeling of the uterine spiral arterioles, which is essential for placental perfusion and successful pregnancy. The proper interaction between maternal KIRs and their ligands human leukocyte antigen (HLA) class I molecules, expressed by the extravillous trophoblast cells, is crucial in this process. KIRs are a complex family that includes both activator and inhibitory receptors. The activation profile is genetically determined in each individual and leads to diverse levels of functionality for NK and T cells on engagement with specific HLA class I molecules. An association between different KIR alleles and HLA molecules has been reported in pregnancy complications, supporting the idea of a relevant role of these receptors in successful pregnancy.

A Detailed View of KIR Haplotype Structures and Gene Families as Provided by a New Motif-Based Multiple Sequence Alignment

“…Whether or not these transmembrane receptors on natural killer (NK) cells bind with peptide-bound human leukocyte antigen (HLA) class I molecules determines how they help educate, activate, and inhibit NK cell functionality, including cytotoxicity and cytokine release. The accumulated evidence seems to indicate that KIR evolved with HLA to balance its pathogen defense effects with its effects on reproduction via the embryo-uterus interface (1)(2)(3). KIR effects are generally tissue-specific and tissue-variable.…”

Immunity at maternal–fetal interface: KIR/HLA (Allo)recognition*

“…KIR2DL4 is member of the KIR family, an evolutionarily conserved and has a structure, localization, and function that differs from that of other KIRs 108,109 . Depending on the circumstances, KIR2DL4 may mediate inhibitory or activating signals 110 . KIR2DL4 emerges as an activation receptor specific for soluble HLA‐G, a unique molecule expressed by human trophoblasts.…”

Immunological Testing in Assisted Reproductive Technology

“…KIR genes expressing surface receptors are highly variable among individuals. 21 Two primary haplotypes exist: predominantly inhibitory KIR-A and predominantly activatory KIR-B. 21 In addition, variability is seen within HLA-C, 20 and these variations are necessary for a wide immune response.…”

“…HLA-G binding induces uNK to upregulate genes involved in proangiogenic response. 21 uNK cells also play a role in senescence of stromal cells; in particular, clearance of senescent stromal cells by uNK cells has been described. 30 A balance between senescence and proliferation of stromal cells is important in supporting implantation, maintaining appropriate structural integrity of the endometrium, and menstruation.…”