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Ly49 cluster sequence analysis in a mouse model of diabetes: an expanded repertoire of activating receptors in the NOD genome.

ABSTRACT: The mouse Ly49 and human killer cell immunoglobulin-like receptors (KIR) gene clusters encode activating and inhibitory class I MHC receptors on natural killer (NK) cells. A direct correlation between the presence of multiple activating KIR and various human autoimmune diseases including diabetes has been shown. Previous studies have implicated NK cell receptors in the development of diabetes in the non-obese diabetic (NOD) inbred mouse strain. To assess the contribution of Ly49 to NOD disease acceleration the Ly49 gene cluster of these mice was sequenced. Remarkably, the NOD Ly49 haplotype encodes the largest haplotype and the most functional activating Ly49 of any known mouse strain. These activating Ly49 include three Ly49p-related and two Ly49h-related genes. The NOD cluster contains large regions highly homologous to both C57BL/6 and 129 haplotypes, suggesting unequal crossing over as a mechanism of Ly49 haplotype evolution. Interestingly, the 129-like region has duplicated in the NOD genome. Thus, the NOD Ly49 cluster is a unique mix of elements seen in previously characterized Ly49 haplotypes resulting in a disproportionately large number of functional activating Ly49 genes. Finally, the functionality of activating Ly49 in NOD mice was confirmed in cytotoxicity assays.

SUBMITTER: Belanger S

PROVIDER: S-EPMC2678550 | biostudies-literature | 2008 Sep

REPOSITORIES: biostudies-literature

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Ly49 cluster sequence analysis in a mouse model of diabetes: an expanded repertoire of activating receptors in the NOD genome.

Belanger S S Tai L-H LH Anderson S K SK Makrigiannis A P AP

Genes and immunity 20080605 6

The mouse Ly49 and human killer cell immunoglobulin-like receptors (KIR) gene clusters encode activating and inhibitory class I MHC receptors on natural killer (NK) cells. A direct correlation between the presence of multiple activating KIR and various human autoimmune diseases including diabetes has been shown. Previous studies have implicated NK cell receptors in the development of diabetes in the non-obese diabetic (NOD) inbred mouse strain. To assess the contribution of Ly49 to NOD disease a ...[more]

PMID: 18528402

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Project description:In humans, specific patterns of killer immunoglobulin-like receptors (KIRs) expressed by uterine natural killer (uNK) cells are linked through HLA-C with pregnancy complications (infertility, recurrent spontaneous abortion, intrauterine growth restriction and preeclampsia). To identify mechanisms underpinning the associations between NK cell activation and pregnancy success, pregnancies were studied in mice with genetic knockdown (KD) of the MHC-activated Ly49 receptor gene family. B6.Ly49(KD) pregnancies were compared to normal control B6.Ly49(129) and C57BL/6 (B6) pregnancies. At mid-pregnancy (gestation day (gd9.5)), overall uNK cell (TCRβ(-)CD122(+)DBA(+)DX5(-) (DBA(+)DX5(-))) and TCRβ(-)CD122(+)DBA(-)DX5(+) (DBA(-)DX5(+))) frequencies in pregnant uterus were similar between genotypes. Ly49(KD) lowered the normal frequencies of Ly49(+) uNK cells from 90.3% to 47.8% in DBA(-)DX5(+) and 78.8% to 6.3% in DBA(+)DX5(-) uNK cell subtypes. B6.Ly49(KD) matings frequently resulted in expanded blastocysts that did not implant (subfertility). B6.Ly49(KD) mice that established pregnancy had gestational lengths and litter sizes similar to controls. B6.Ly49(KD) neonates, however, were heavier than controls. B6.Ly49(KD) implantation sites lagged in early (gd6.5) decidual angiogenesis and were deficient in mid-pregnancy (gd10.5) spiral arterial remodelling. Ultrastructural analyses revealed that B6.Ly49(KD) uNK cells had impaired granulogenesis, while immunocytochemistry revealed deficient vascular endothelial cell growth factor (VEGFA) production. Perforin and IFNG expression were normal in B6.Ly49(KD) uNK cells. Thus, in normal mouse pregnancies, Ly49 receptor signaling must promote implantation, early decidual angiogenesis and mid-pregnancy vascular remodelling. Disturbances in these functions may underlie the reported genetic associations between human pregnancy complications and the inability of specific conceptus MHCs to engage activating KIR on uNK cells.

Dataset Information

Ly49 cluster sequence analysis in a mouse model of diabetes: an expanded repertoire of activating receptors in the NOD genome.

Publications

Ly49 cluster sequence analysis in a mouse model of diabetes: an expanded repertoire of activating receptors in the NOD genome.

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