High-Resolution Genetic and Phenotypic Analysis of KIR2DL1 Alleles and Their Association with Pre-Eclampsia.
Journal of immunology (Baltimore, Md. : 1950)
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Huhn, O., Chazara, O., Ivarsson, M. A., Retière, C., Venkatesan, T. C., Norman, P. J., Hilton, H. G., et al. (2018). High-Resolution Genetic and Phenotypic Analysis of KIR2DL1 Alleles and Their Association with Pre-Eclampsia.. Journal of immunology (Baltimore, Md. : 1950), 201 (9), 2593-2601. https://doi.org/10.4049/jimmunol.1800860
Killer-cell immunoglobulin-like receptor (KIR) genes are inherited as haplotypes. They are expressed by NK cells and linked to outcomes of infectious diseases and pregnancy in humans. 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.
This work was funded by the Wellcome Trust (Grant 200841/Z/16/Z to FC and AM), the Medical Research Council (Grant MR/P001092/1 to AS), the National Institutes of Health (Grant NIH U01 AI090905 to PJN and R01 AI17892 to PP) and the Cambridge NIHR BRC Cell Phenotyping Hub (to FC). The POPS study is funded by the Women’s Health theme of the NIHR Cambridge Biomedical Research Centre and the Stillbirth and Neonatal Death Society (SANDS). OH was supported by a MedImmune-Cambridge PhD fellowship. OC was supported by a CTR Next Generation Fellowship.
Medical Research Council (MR/P001092/1)
Wellcome Trust (200841/Z/16/Z)
Medical Research Council (G0901682)
European Research Council (695551)
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External DOI: https://doi.org/10.4049/jimmunol.1800860
This record's URL: https://www.repository.cam.ac.uk/handle/1810/285151