Molecular and Genetic Basis for Strain-Dependent NK1.1 Alloreactivity of Mouse NK Cells

Carlyle, James R.; Mesci, Aruz; Ljutic, Belma; Bélanger, Simon; Tai, Lee-Hwa; Rousselle, Etienne; Troke, Angela D.; Proteau, Marie-France; Makrigiannis, Andrew P.

doi:10.4049/jimmunol.176.12.7511

Cited by 117 publications

(119 citation statements)

References 37 publications

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“…This is in line with an early characterization of NKR-P1B as an alloantigen [19]. It is also reminiscent of the situation in the mouse, where the Nkrp1b and -d genes were shown to represent two divergent alleles at the same locus [20]. Hence, we suggest that NKR-P1C is renamed as NKR-P1B PVG or NKR-P1B and will refer to it as such in the following.…”

Section: Introductionsupporting

confidence: 72%

Two major groups of rat NKR‐P1 receptors can be distinguished based on chromosomal localization, phylogenetic analysis and Clr ligand binding

et al. 2009

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A major subset of non-alloreactive NK cells in PVG strain rats is generally low in Ly49 receptors, but expresses the rat NKR-P1B PVG receptor (previously termed NKR-P1C). The NKR-P1B 1 NK subset is inhibited by a non-polymorphic target cell ligand, which we have shown here to be a C-type lectin-related molecule (Clr). Clr11 ligates two divergent NKR-P1B alleles as judged by an NFAT-driven reporter assay, and inhibits NK-cell cytotoxicity of NKR-P1B 1 NK cells. Clr11 also interacts with the prototypic NKR-P1A receptor and exerts a stimulatory influence on NK lysis. NKR-P1A and B are encoded by adjacent genes in the proximal part of the NK gene complex and show close sequence homology in their extracellular region. They diverge from another pair, NKR-P1F and -G, which is encoded by a second, distal Nkrp1 gene cluster. NKR-P1F and -G bind an overlapping panel of Clr ligands, but not Clr11. Rat Clr molecules appear to be constitutively expressed by hematopoietic cells; expression in tumor cell lines is more variable. The data show the existence of two phylogenetic groups of NKR-P1 molecules, which demonstrate conservation of ligand-binding properties independent of signaling function.Key words: Cytotoxicity . NK cells . Receptor . Rodent Introduction NK cells express several families of killer cell lectin-like receptors (KLR). These are type II transmembrane proteins encoded by the NK gene complex (NKC), which is located on chromosome 4 in the rat [1,2]. The NKR-P1 molecules (KLRB or CD161) were among the first KLR to be characterized, but their function long remained elusive [3][4][5]. Although the NKR-P1 family has expanded to include both activating and inhibitory members in rodents, it consists of only one member in several other mammalian species, including in human [6]. The nature of their ligands has been controversial [7,8], but it has recently been shown that members of another KLR-related receptor family, the C-type lectin-related (Clr) molecules [9], also termed C-type lectin 2D (CLEC2D), can act as ligands for certain NKR-P1 molecules [10,11]. The Clr gene family also shows considerable expansion in rodents and the Clr genes are interspersed with the Nkrp1 genes in the proximal (centromeric) part of the NKC. A recent analysis concluded that there are 11 Clr/Clec2d genes in the rat BN strain genome, which were numbered consecutively from proximal to distal. One of these (Clr8) is most likely only a gene fragment, which could have been excluded, but we will nevertheless adhere to the Clr numbering suggested by Hao et al. [6].In the mouse, the inhibitory NKR-P1B and -D receptors both bind Clrb (also termed Ocil). Clrb is constitutively expressed by hematopoietic cells and inhibits cytolytic activity of NKR-P1B/ D-expressing NK cells [10,11]. The activating NKR-P1F receptor has been shown to bind another Clr molecule, Clrg, by the use of a reporter assay and soluble recombinant proteins [11] functional consequence of this interaction remains obscure. In human, the NKR-P1A receptor binds a Clr orthologue term...

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Section: Introductionsupporting

confidence: 72%

Two major groups of rat NKR‐P1 receptors can be distinguished based on chromosomal localization, phylogenetic analysis and Clr ligand binding

et al. 2009

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“…Semiquantitative RT-PCR was performed on serial 5-fold dilutions of cDNA with the use of gene-specific primers. 5,[16][17][18] Semiquantitative PCR to verify the presence of the concatemer was performed on genomic DNA with the use of the following primers as depicted in Figure 1D: 5Ј forward out, 5Ј-CCAGTCCTAAATCTGATAGG; 5Ј forward in, 5Ј-GCTGGCCGTTATCATGTTGA; 5Ј reverse, 3Ј-ACAGTCTCCCTTGCCTGTAG; 3Ј forward, 5Ј-GGTATGGTTTAAC-CCACTCA; 3Ј reverse in, 3Ј-GGTGCCTCGAGTGGTTTCTA; and 3Ј reverse out, 3Ј-TTCTGTAGCCAGCTTCTCTG.…”

Section: Cellsmentioning

confidence: 99%

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

Bélanger

Rahim

et al. 2012

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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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“…However, NK cells in BALB/c mice express a functional Nkpr1 gene that differs from the B6 allele in that it does not contain the NK1.1 alloantigen and therefore is not recognized by anti-NK1.1 mAb (62) and BALB/c mice, we tested whether GM1 and ASGM1 expression by NK and T cells differs between BALB/c and B6 mice. First, we determined the co-expression of CD49b and NK1.1 by NK cells in the lungs of RSV-infected B6 mice at 6 d.p.i.…”

Section: Nk and Cd8 ϩ T-cell Gm1 And Asgm1 Expression In Balb/c And Bmentioning

confidence: 99%

Differential Regulation of GM1 and Asialo-GM1 Expression by T Cells and Natural Killer (NK) Cells in Respiratory Syncytial Virus Infection

et al. 2008

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We previously reported that respiratory syncytial virus (RSV) infection increases lung CD8 ϩ T cell GM1 expression. The related lipid asialo-GM1 (ASGM1) is expressed by T cells in viral infection and by natural killer (NK) cells. The in vivo co-expression of GM1 and ASGM1 by immune cells is not defined. Here we analyzed lung lymphocyte GM1 and ASGM1 expression in RSV-infected mice. GM1 and ASGM1 were coordinately upregulated by activated CD8 ϩ T cells in RSV-infected BALB/c and C57BL/6 mice. In contrast, RSV infection had no effect on constitutively high NK cell GM1 expression, while increasing NK cell ASGM1 expression. GM1 and ASGM1 co-localized in lipid raft structures in NK and CD8 ϩ T cells sorted from the lungs of RSV-infected mice. Anti-ASGM1 Ab treatment of RSV-infected BALB/c mice depleted GM1/ASGM1-expressing NK cells and GM1/ASGM1-expressing T cells, reduced lung IFN-␥ levels, increased viral load, delayed viral clearance, and reduced illness. STAT1 Ϫ/Ϫ mice are more susceptible to RSV replication and disease than wild-type mice. In RSV-infected STAT1 Ϫ/Ϫ mice, anti-ASGM1 Ab altered cytokine levels, but in contrast to BALB/c mice, antibody treatment had no effect on viral load or illness. Taken together, GM1 and ASGM1 expression are differentially regulated by T and NK cells in RSV infection. Also, GM1/ASGM1-expressing cells are important for control of RSV in BALB/c mice, whereas STAT1 Ϫ/Ϫ mice clear RSV by an alternative pathway. 327

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Molecular and Genetic Basis for Strain-Dependent NK1.1 Alloreactivity of Mouse NK Cells

Cited by 117 publications

References 37 publications

Two major groups of rat NKR‐P1 receptors can be distinguished based on chromosomal localization, phylogenetic analysis and Clr ligand binding

Two major groups of rat NKR‐P1 receptors can be distinguished based on chromosomal localization, phylogenetic analysis and Clr ligand binding

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

Differential Regulation of GM1 and Asialo-GM1 Expression by T Cells and Natural Killer (NK) Cells in Respiratory Syncytial Virus Infection

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