Disease relevance of Klra

• Epistasis between mouse Klra and major histocompatibility complex class I loci is associated with a new mechanism of natural killer cell-mediated innate resistance to cytomegalovirus infection [1].
• Critical Residues at the Ly49 Natural Killer Receptor's Homodimer Interface Determine Functional Recognition of m157, a Mouse Cytomegalovirus MHC Class I-Like Protein [2].
• Adhesion to class I molecules was not found with T lymphomas lacking Ly-49 expression [3].
• Therefore, we have correlated the frequencies of cells expressing the pan-NK marker DX5 and subsets bearing inhibitory Ly-49 receptors with worm survival and cytokine production during infection with Litomosoides sigmodontis in BALB/c mice (H2(d)), the only fully permissive model of filariasis [4].
• Ly-49 can be expressed in interspecies hybridoma cells resulting from the fusion of Ly-49 negative lymphoid cells from normal mice and Ly-49 negative T cells from the rat thymoma W/Fu(C58NT)D (C58) [5].

High impact information on Klra

• A transcript map of the region identified 19 genes, including members of the killer cell lectin-like receptor family a (Klra, formerly Ly49; refs. 9-12), which encode inhibitory or activating NK cell receptors that interact with MHC class I molecules [6].
• Expression of Ly49A and Ly49C, another member of the Ly49 family with distinct MHC specificity, define subpopulations of NK cells that are only partly overlapping [7].
• Identification of probabilistic transcriptional switches in the Ly49 gene cluster: a eukaryotic mechanism for selective gene activation [8].
• Here we employ a semiquantitative cell-cell adhesion assay as well as class I/peptide tetramers to provide a comprehensive analysis of specificities of Ly49 receptors for class I MHC molecules in eight MHC haplotypes [9].
• The tetramer studies demonstrated that neither glycosylation nor coreceptors were necessary for class I binding to Ly49 receptors and uncovered peptide-specific recognition by a Ly49 receptor [9].

Biological context of Klra

• Hence, the structural constraints on dimerization geometry may be relatively relaxed within the Ly49 family [10].
• In this study, the complete BALB/c Ly49 gene cluster has been sequenced and found to contain six functional genes and two pseudogenes [11].
• The Cmv1 host resistance locus is closely linked to the Ly49 multigene family within the natural killer cell gene complex on mouse chromosome 6 [12].
• 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 [11].
• Altered phenotype and function of natural killer cells expressing the major histocompatibility complex receptor Ly-49 in mice transgenic for its ligand [13].

Anatomical context of Klra

• Also, administration of LTbetaR-immunoglobulin (Ig), which acts as a soluble receptor for LTalpha1beta2, resulted in reduced NK cell percentages but did not influence the Ly49 and CD94/NKG2 receptor acquisition on remaining NK cells [14].
• A crucial step in murine natural killer (NK) cell development, mediated by bone marrow stromal cells, is the induction of Ly49 and CD94/NKG2 receptor expression [14].
• NK cell function is regulated by Ly49 receptors in mice and killer cell Ig-like receptors in humans [2].
• Expansion and function of CD8+ T cells expressing Ly49 inhibitory receptors specific for MHC class I molecules [15].
• By using primers based on the consensus sequences of the genomic clones, expression of Ly-49-related genes was detected by the polymerase chain reaction in various organs, including lung, kidney, liver, spleen, and thymus [16].

Associations of Klra with chemical compounds

• Differential tyrosine phosphorylation of inhibitory versus activating Ly-49 receptor proteins and their recruitment of SHP-1 phosphatase [17].
• The acquisition of one Ly-49 receptor, Ly-49A is strictly dependent on the transcriptional trans-acting factor T cell-specific factor-1 (TCF-1) [18].
• In the present study, we haveidentified this glycoprotein as a novel rat Ly49 receptor (Ly49i2) containing an immunoreceptor tyrosine-based inhibitory motif [19].
• We recently reported that IL-7 preferentially promotes the in vitro expansion of a discrete MHC class I-dependent lymphocyte subset comprising both CD4+ and CD4-CD8- TCR alpha beta + cells bearing several NK cells markers such NK1.1 and Ly-49 [20].
• Although we cannot exclude the possibility that NK cells participate in tumor cell killing in vivo, the presence of NK markers such as DX5, asialo GM1, Ly49, and CD94, and NKG2D on large numbers of eosinophils activated by eotaxin suggests that eosinophils function in such suppression of tumor cell growth [21].

Regulatory relationships of Klra

• These data suggest that LTbetaR-mediated signals regulate Ly49 expression at least in part through the activation of IL-15 [22].

Other interactions of Klra

• These results indicate that LTbetaR-mediated signals are not required for Ly49 and CD94/NKG2 receptor acquisition [14].
• A role for lymphotoxin in the acquisition of Ly49 receptors during NK cell development [22].
• Murine homologs of human NKG2 family members have not yet been identified, but we report here the existence of a murine NKG2D-like sequence that also maps to the murine NK complex near CD94 and Ly49 family members [23].
• TCR and CD28 were re-expressed more rapidly than the inhibitory NK-cell receptors CD94/NKG2A and Ly49, temporally rendering the primed iNKT cells hyperreactive to ligand restimulation [24].
• This inhibition of IFN-gamma production by MHC class I was independent of Ly-49 or CD94/NKG2A expression on NK cells [25].

Analytical, diagnostic and therapeutic context of Klra

• Increased bone marrow allograft rejection by depletion of NK cells expressing inhibitory Ly49 NK receptors for donor class I antigens [26].
• By examination of DNA from informative recombinant inbred mice with Southern blot analysis, we have determined that mNKR-P1 is encoded by a distinct gene that is genetically linked to the Ly-49 locus, lying within 0.5 centi-Morgan (cM) of Ly-49 [27].
• We developed a single-cell RT-PCR method to analyze expression of all known Ly49 and NKG2A genes in individual NK cells and determined the receptor repertoires of NK cells from adult and neonatal (1-wk-old) C57BL/6 mice [28].
• METHODS: We developed Ly49 receptor transgenic mice and studied the function of Ly49I(B6) in FVB.Ly49I(B6) transgenic mice using bone marrow transplantation assays to determine additional functional ligands for Ly49I(B6) [29].
• These results show that the addition of a small number of paraformaldehyde fixed YAC cells to spleen cell cultures undergoing IL2 activation, resulted in a significant upregulation of Ly49 receptors and this process was dependent upon cell proliferative activity [30].

References