Uterine natural killer cells

Large granular lymphocytes surround a uterine artery in the four-toed

elephant shrew. Courtesy of Dr. Dominic Oduor-Okelo.

Large granular lymphocytes occur in the uterus of many mammals. Often they are associated with uterine blood vessels. In rodents and primates they are known to be natural killer (NK) cells.

Early in human pregnancy, around 70% of the immune cells in the uterus are uterine NK cells. Their phenotype is different from that of circulating NK cells. Their functions include remodelling spiral arteries and regulating trophoblast invasion. Uterine NK cells also occur in the mouse and other muroid rodents, where they are essential for widening the arteries: this fails to occur in transgenic strains that lack NK cells. 

Natural killer cell receptors

NK cells are important in the recognition of self and non-self. Surveillance of the highly polymorphic major histocompatibility complex (MHC) class I antigens (in humans HLA for human leukocyte antigens) involves an equally polymorphic system of killer immunoglobulin-like receptors (KIRs). KIRs seem to be involved in regulating the depth of trophoblast invasion. Peter Parham and Ashley Moffett have just published a review of the topic that can be highly recommended. If you are interested and motivated yet—like me—struggle to understand the interplay of HLAs and KIRs, this is the place to go.

KIR genes are part of the leukocyte receptor complex on chromosome 19. A couple of additional receptors, NKG2D and CD94 (or NKG2A) belong to the killer C-lectin like receptors coded by genes in the natural killer complex on chromosome 12.

Now for what elsewhere has been called “an inconvenient truth.” The mouse does not have an expanded family of KIRs. Indeed, it has only one functional KIR gene and that has translocated to the X chromosome. Muroid rodents instead have chosen to expand a family of lectin-like receptors named Ly49. Apart from being structurally different from KIRs, these receptors bind to a different site on the MHC molecule.

Mismatching of HLA-C variants and KIR haplotypes is associated with increased incidences of recurrent abortion, fetal growth restriction and preeclampsia. This system cannot be explored in the mouse.