Allelic exclusion of Ly49-family genes encoding class I MHC-specific receptors on NK cells

Held, Werner; Roland, Jacques; Raulet, David H.

doi:10.1038/376355a0

Cited by 177 publications

(142 citation statements)

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“…Allelic exclusion, where only one or the other allele of Ly-49 genes is expressed in the majority of F 1 NK cells, has been observed (47)(48)(49)(50). The functional significance of Ly-49 allelic exclusion is unknown.…”

Section: Discussionmentioning

confidence: 99%

Allelic Variation in the Ectodomain of the Inhibitory Ly-49G2 Receptor Alters Its Specificity for Allogeneic and Xenogeneic Ligands

Silver

Lavender

Gong

et al. 2002

The Journal of Immunology

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The Ly-49 multigene receptor family regulates mouse NK cell functions. A number of Ly-49 genes exhibit allelic variation, but the functional significance of allelic differences in extracellular domains of Ly-49 receptors regarding ligand specificity is largely unknown. Amino acid differences exist in the extracellular domains of the B6 and BALB/c allele products of the inhibitory Ly-49G receptor. We constructed chimeric Ly-49 receptors consisting of common cytoplasmic and transmembrane regions of the activating Ly-49W receptor fused with the ectodomains of the B6 and BALB/c alleles of Ly-49G. Expression of these chimeras in the RNK-16 rat NK cell line allowed us to study the specificity of inhibitory receptor ectodomains as they stimulated NK lytic activity. We found that the ectodomain of the BALB/c allele of Ly-49G recognizes both H-2Dd and Dk class I MHC alleles, whereas the ectodomain of the B6 allele of Ly-49G recognizes Dd, and not Dk. The specificity for Dk as well as Dd of the wild-type Ly-49GBALB/c allele product was confirmed with RNK-16 transfectants of this inhibitory receptor. Furthermore, the ectodomain of the Ly-49GBALB/c allele recognizes a distinct repertoire of xenogeneic ligands that only partially overlaps with that recognized by Ly-49GB6. Our results indicate that allelic variation in Ly-49 extracellular domains can have functional significance by altering Ly-49 receptor specificity for mouse class I MHC and xenogeneic ligands.

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Section: Discussionmentioning

confidence: 99%

Allelic Variation in the Ectodomain of the Inhibitory Ly-49G2 Receptor Alters Its Specificity for Allogeneic and Xenogeneic Ligands

Silver

Lavender

Gong

et al. 2002

The Journal of Immunology

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“…[3][4][5] Cloning and sequencing of Ly49 cDNAs showed that BALB/c NK cells share at least three Ly49-related sequences or alleles with B6 mice: Ly49a, c, and g, although the alleles have diverged and contain a significant number of differences, resulting in several amino-acid substitutions. [6][7][8] The novel activating Ly49L receptor was also found to be expressed in BALB/c mice, but was first identified in the Ly49 haplo-identical CBA and C3H mouse strains. 8,9 The finding of Ly49L supported the contention that all activating receptors have an inhibitory counterpart with a highly similar extracellular domain that has probably arisen by gene hybridization between two different Ly49 genes.…”

Section: Introductionmentioning

confidence: 99%

Complete elucidation of a minimal class I MHC natural killer cell receptor haplotype

Dewar

Ml³

et al. 2005

Genes Immun

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The BALB/c inbred mouse is widely used in models of infectious disease, transplantation, and cancer. The differences in the immune responses of BALB/c compared to C57BL/6 mice are especially valuable for the identification of immune regulation genes. One striking immune variance between these mice is in the function of natural killer (NK) cells, and there is strong evidence implicating differential expression of Ly49 genes. In this study, the complete BALB/c Ly49 gene cluster has been sequenced and found to contain six functional genes and two pseudogenes. Compared to C57BL/6 mice, there is a 200 kb region absent in the BALB/c cluster including a complete lack of Ly49h-related genes, which explains the increased susceptibility of BALB/c to cytomegalovirus infection. In addition, there is no BALB/c Ly49d allele, explaining the inability of BALB/c NK cells to kill certain tumor cells. The Ly49 region has now been sequenced in three different inbred mouse strains, and comparisons indicate that the evolution of each haplotype is not straightforward and has involved large-scale deletions/ insertions, gene recombination, and unequal crossing over between divergent haplotypes. This study confirms that relatively small murine class I MHC receptor haplotypes exist, analogous to observations made of human killer cell Ig-like receptor gene haplotypes.

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“…Interestingly, individual alleles of these Ly49 genes are stochastically chosen for stable expression in different NK cells. Monoallelic expression of the Ly49 genes is therefore thought to be essential for generating a diverse repertoire of NK cell receptors (Held et al, 1995;Held and Raulet, 1997;Held and Kunz, 1998). More recently, the analysis of wild-type T cells and heterozygous mutant mice has revealed that individual alleles of the IL-2 and IL-4 genes are independently regulated by a stochastic process in T helper cells (Holländer et al, 1998;Bix and Locksley, 1998;Rivière et al, 1998).…”

Section: Monoallelic Expression As a Results Of Stochastic Activation mentioning

confidence: 99%

Monoallelic Expression of Pax5: A Paradigm for the Haploinsufficiency of Mammalian Pax Genes?

Nutt¹,

Busslinger²

1999

Biological Chemistry

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It is generally assumed that most mammalian genes are transcribed from both alleles. Hence, the diploid state of the genome offers the advantage that a lossof-function mutation in one allele can be compensated for by the remaining wild-type allele of the same gene. Indeed, the vast majority of human disease syndromes and engineered mutations in the mouse genome are recessive, indicating that recessiveness is the 'default' state. However, a minority of genes are semidominant, as heterozygous loss-of-function mutation in these genes leads to phenotypic abnormalities. This condition, known as haploinsufficiency, has been described for five of the nine mammalian Pax genes, which are associated with mouse developmental mutants and human disease syndromes. Recently we have reported that the Pax5 gene is subject to allelespecific regulation during B cell development. Pax5 is predominantly transcribed from only one of its two alleles in early B-lymphoid progenitors and mature B cells, while it transiently switches to a biallelic mode of transcription in pre-B and immature B cells. As a consequence, B-lymphoid tissues are mosaic with regard to the transcribed allele, and heterozygous mutation of Pax5 therefore results in deletion of B lymphocytes expressing only the mutant allele. The allele-specific regulation of Pax5 raises the intriguing possibility that monoallelic expression may also be the mechanism causing the haploinsufficiency of other Pax genes. In this review, we discuss different models accounting for the haploinsufficiency of mammalian Pax genes, provide further evidence in support of the allele-specific regulation of Pax5 and discuss the implication of these findings in the context of the recent literature describing the stochastic and monoallelic activation of other hematopoietic genes. Key words: B cell development / Haploinsufficiency / Monoallelic expression / Pax5 / Single-cell RT-PCR. Models to Account for HaploinsufficiencyThe genetic term haploinsufficiency describes a situation where a null mutation in one allele of a gene results in a mutant phenotype despite the presence of the second, wildtype allele. A haploinsufficient gene therefore fulfills its normal function only in the presence of both wild-type alleles, and hence its activity is highly sensitive to gene dosage.Haploinsufficiency is a relatively rare genetic phenomenon in mammals, as the majority of human disease syndromes and engineered mouse mutation are recessive (Fisher and Scambler, 1994). Nevertheless, a growing number of mammalian transcription factor genes have recently been reported to be haploinsufficient (Fisher and Scambler, 1994;Engelkamp and van Heyningen, 1996). While several explanations for haploinsufficiency have been suggested (Wilkie, 1994;Read, 1995), we will discuss below only the three most likely models. The Protein-Protein Interaction ModelTranscription factors commonly depend on the interaction with partner proteins to fulfill their functions in gene activation and repression. Both positive and negative control b...

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Allelic exclusion of Ly49-family genes encoding class I MHC-specific receptors on NK cells

Cited by 177 publications

References 27 publications

Allelic Variation in the Ectodomain of the Inhibitory Ly-49G2 Receptor Alters Its Specificity for Allogeneic and Xenogeneic Ligands

Allelic Variation in the Ectodomain of the Inhibitory Ly-49G2 Receptor Alters Its Specificity for Allogeneic and Xenogeneic Ligands

Complete elucidation of a minimal class I MHC natural killer cell receptor haplotype

Monoallelic Expression of Pax5: A Paradigm for the Haploinsufficiency of Mammalian Pax Genes?

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