Evolution of the Ly49 and Nkrp1 recognition systems

Carlyle, James R.; Mesci, Aruz; Fine, Jason H.; Chen, Peter; Bélanger, Simon; Tai, Lee-Hwa; Makrigiannis, Andrew P.

doi:10.1016/j.smim.2008.05.004

Cited by 91 publications

(134 citation statements)

References 85 publications

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“…In contrast, the 129-Ly49 gene cluster encodes three activating receptors (Ly49R, U, P), nine inhibitory receptors (Ly49Q 1 , E, V, EC 2 , S, T, I 1 , G, O) and seven pseudogenes. 29 Mice with broad-spectrum KD (knockdown) of Ly49 expression (B6.Ly49 KD , also referred to as NKC KD ), were created and characterized by our group. 30 Approximately 80% of Ly49 receptor expression is reduced in NK cells in the spleens of these mice due to a concatemer insertion of the gene-targeting vector in the Ly49 region of the NKC.…”

Section: Introductionmentioning

confidence: 99%

Ly49 receptors activate angiogenic mouse DBA+ uterine natural killer cells

Lima

Rahim

et al. 2014

Cell Mol Immunol

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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 (TCRb 2 CD122 1 DBA 1 DX5 2 (DBA 1 DX5 2 )) and TCRb 2 CD122 1 DBA 2 DX5 1 (DBA 2 DX5 1 )) frequencies in pregnant uterus were similar between genotypes. Ly49 KD lowered the normal frequencies of Ly49 1 uNK cells from 90.3% to 47.8% in DBA 2 DX5 1 and 78.8% to 6.3% in DBA 1 DX5 2 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.

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Section: Introductionmentioning

confidence: 99%

Ly49 receptors activate angiogenic mouse DBA+ uterine natural killer cells

Lima

Rahim

et al. 2014

Cell Mol Immunol

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“…The Klra (Ly49) gene family is highly polymorphic, with significant variation in gene content between mouse strains. 4 The Klra haplotype of 129-strain mice contains 19 genes that encode 3 activating and 9 inhibitory receptors; the remaining genes are pseudogenes. 5 Ly49 receptors are divided into 2 main groups: activating and inhibitory receptors.…”

Section: Introductionmentioning

confidence: 99%

Impaired natural killer cell self-education and “missing-self” responses in Ly49-deficient mice

Bélanger

Rahim

et al. 2012

Blood

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Ly49-mediated recognition of MHC-I molecules on host cells is considered vital for natural killer (NK)–cell regulation and education; however, gene-deficient animal models are lacking because of the difficulty in deleting this large multigene family. Here, we describe NK gene complex knockdown (NKCKD) mice that lack expression of Ly49 and related MHC-I receptors on most NK cells. NKCKD NK cells exhibit defective killing of MHC-I–deficient, but otherwise normal, target cells, resulting in defective rejection by NKCKD mice of transplants from various types of MHC-I–deficient mice. Self–MHC-I immunosurveillance by NK cells in NKCKD mice can be rescued by self–MHC-I–specific Ly49 transgenes. Although NKCKD mice display defective recognition of MHC-I–deficient tumor cells, resulting in decreased in vivo tumor cell clearance, NKG2D- or antibody-dependent cell-mediated cytotoxicity–induced tumor cell cytotoxicity and cytokine production induced by activation receptors was efficient in Ly49-deficient NK cells, suggesting MHC-I education of NK cells is a single facet regulating their total potential. These results provide direct genetic evidence that Ly49 expression is necessary for NK-cell education to self–MHC-I molecules and that the absence of these receptors leads to loss of MHC-I–dependent “missing-self” immunosurveillance by NK cells.

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“…The receptor systems for MHC-I have undergone considerable selective pressure and have diverged significantly between species, and this divergence is exemplified by the differences between humans and rodents. The receptors that bind to classical MHC-I in humans belong to the Ig superfamily and are named killer cell Ig-like receptors (5); in contrast, the parallel receptors in mice belong to the C-type lectin family of receptors and are called Ly49 receptors (6). Mice and humans share the CD94/NKG2 heterodimeric C-type lectin-like receptors that detect nonclassical MHC-I (HLA-E and Qa1) (2).…”

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confidence: 99%

Poxvirus Infection-Associated Downregulation of C-Type Lectin-Related-b Prevents NK Cell Inhibition by NK Receptor Protein-1B

Williams

Wilson

Davidson

et al. 2012

The Journal of Immunology

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Innate immune recognition of virus-infected cells includes NK cell detection of changes to endogenous cell-surface proteins through inhibitory receptors. One such receptor system is the NK cell receptor protein-1B (NKR-P1B) and its ligand C-type lectin-related-b (Clr-b). NKR-P1B and Clr-b are encoded within the NK cell gene complex, a locus that has been linked to strain-dependent differences in susceptibility to infection by poxviruses. In this study, we report the impact of vaccinia virus (VV) and ectromelia virus infection on expression of Clr-b and Clr-b–mediated protection from NK cells. We observed a loss of Clr-b cell-surface protein upon VV and ectromelia virus infection of murine cell lines and bone marrow-derived macrophages. The reduction of Clr-b is more rapid than MHC class I, the prototypic ligand of NK cell inhibitory receptors. Reduction of Clr-b requires active viral infection but not expression of late viral genes, and loss of mRNA appears to lag behind loss of Clr-b surface protein. Clr-b–mediated protection from NK cells is lost following VV infection. Together, these results provide the second example of Clr-b modulation during viral infection and suggest reductions of Clr-b may be involved in sensitizing poxvirus-infected cells to NK cells.

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Evolution of the Ly49 and Nkrp1 recognition systems

Cited by 91 publications

References 85 publications

Ly49 receptors activate angiogenic mouse DBA+ uterine natural killer cells

Ly49 receptors activate angiogenic mouse DBA+ uterine natural killer cells

Impaired natural killer cell self-education and “missing-self” responses in Ly49-deficient mice

Poxvirus Infection-Associated Downregulation of C-Type Lectin-Related-b Prevents NK Cell Inhibition by NK Receptor Protein-1B

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