High-resolution genetic and phenotypic analysis of KIR2DL1 alleles and their association with pre-eclampsia

Abstract

Killer-cell immunoglobulin-like receptor (KIR) genes are inherited as haplotypes, expressed by NK cells and linked to outcomes of infectious diseases and pregnancy. Understanding how genotype relates to phenotype is difficult because of the extensive diversity of the KIR family. Indeed, high-resolution KIR genotyping and phenotyping in single NK cells in the context of disease association is lacking. Here, we describe a new method to separate NK cells expressing allotypes of the KIR2DL1 gene carried by the KIR A haplotype (KIR2DL1A) from those expressing KIR2DL1 alleles carried by the KIR B haplotype (KIR2DL1B). We find that in KIR AB heterozygous individuals, different KIR2DL1 allotypes can be detected both in peripheral blood and in uterine single NK cells. Using this new method, we demonstrate that both blood and uterine NK cells co-dominantly express KIR2DL1A and KIR2DL1B allotypes, but with a predominance of KIR2DL1A variants, which associate with enhanced NK cell function. In a case-control study of pre-eclampsia, we show that KIR2DL1A, not KIR2DL1B, associates with increased disease risk. This method will facilitate our understanding of how individual KIR2DL1 allelic variants affect NK cell function and contribute to disease risk.

Distinctive phenotypes and functions of innate lymphoid cells in human decidua during early pregnancy

“…The relative magnitude of response of each subset therefore depends on the specific stimulus. dNK1 cells are once again low responders, consistent with our previous findings that show decreased degranulation of dNK subsets expressing multiple inhibitory NKR in response to K562 35 .…”

“…Despite the weak functional responses to PMA/ionomycin and missing self, the major dILC subset, dNK1, has the potential to respond to invading EVT as they express NKR, including KIR, with ligands on EVT. Immunogenetic and in vitro studies also suggest that binding of KIR on dNK to HLA-C on EVT regulates trophoblast invasion and pregnancy outcome 22,23,35,36 . In pbNK, due to the stochastic nature of KIR expression 37 , individual NK cells can express multiple KIR and acquisition of KIR, CD57 and the loss of NKG2A is associated with NK cell differentiation 38 .…”

“…We have shown that triggering activating KIR2DS1 13,17 and KIR2DS4 15 on dNK to mimic recognition of HLA-C on trophoblast, results in production of cytokines that enhance EVT cell migration in vitro. Furthermore, these activating KIR are associated with a reduced risk of developing pre-eclampsia 15,22,35,36 . When dNK are stimulated by cross-linking KIR2DS4, we now show that increased KIR co-expression on KIR2DS4+dNK is associated with increased cytokine production and degranulation (Fig.…”

Killer‑cell immunoglobulin‑like receptor/human leukocyte antigen‑C combination and ‘great obstetrical syndromes’ (Review)

“…Therefore, future studies on the functionality of KIRs and their ligands should include a higher sample size of RPL couples in a specific area compared with fertile controls (14). A method for estimating KIR2DL1 allotypes coded by the diverse KIR genes has promoted the development of various anti-KIR antibodies and genotyping to indicate that KIR2DL1 on the KIR A instead of the KIR B haplotype is related to the higher probability of PE (77). Mexican researchers collected ten normal pregnant decidua tissues and nine PE decidua samples during cesarean section (22).…”

Report from the Eleventh Killer Immunoglobulin‐like Receptor (KIR) Workshop: Novel insights on KIR polymorphism, ligand recognition, expression and function

“…Notably, some KIR genes are present on both haplotype groups, but allelic variations distinguish A and B KIR haplotypes. Thus, as compared with KIR2DL1 coded by Cen‐B alleles, KIR2DL1 receptors encoded by Cen‐A alleles display brighter cell surface expression, stronger ligand affinity, and higher signaling capability . On the contrary, KIR2DL3 encoded by Cen‐A are characterized by a weaker HLA‐C binding affinity than KIR2DL2 coded by Cen‐B alleles .…”