The Lectin-Like NK Cell Receptor Ly-49A Recognizes a Carbohydrate-Independent Epitope on Its MHC Class I Ligand

Matsumoto, Naoki; Ribaudo, Randall K.; Abastado, Jean-Pierre; Margulies, David H.; Yokoyama, Wayne M.

doi:10.1016/s1074-7613(00)80476-8

Cited by 70 publications

(58 citation statements)

References 50 publications

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“…D d 5 was established by transfecting C1498 cells with wild-type D d expression vector as described previously (23). D d 5 and C1498 cells transfected with D d mutant cDNA were maintained in the same medium supplemented with 0.5 mg/ml G418 sulfate (Life Technologies, Rockville, MD).…”

Section: Cellsmentioning

confidence: 99%

“…Sequences of all mutants were verified by sequencing both strands using ABI373A, ABI377 sequencers, or LS2000 DNA sequencer (Shimadzu, Kyoto, Japan). H-2D d cDNAs with mutations were directionally subcloned into an expression vector pH␤APr-neo driven by human ␤-actin promoter as described previously (23).…”

Section: Site-directed Mutagenesismentioning

confidence: 99%

“…First, recognition of H-2D d by Ly49A is inhibited by the ␣1/␣2 domain-specific Ab 34-5-8S, but not by 34-2-12S Ab, which recognizes ␣3 domain of H-2D d (20). Second, Ly49A recognizes the natural mutant MHC class I molecule dm1, which has ␣1 and the N-terminal half of ␣2 domain of H-2D d and the rest of the regions from H-2L d , which is not a ligand for Ly49A (23). Ly49A recognizes only the peptide-bound form of H-2D d molecules, but there is no apparent specificity for peptides as long as they have the anchoring residues required to bind H-2D d (24,25), in contrast with peptide-specific recognition of MHC class I molecules by TCRs.…”

mentioning

confidence: 97%

“…However, other studies, including investigations by our laboratory, also indicate that there may be functional consequences of H-2D d residues that are not directly contacted by Ly49A. Specifically, we previously localized regions of H-2D d that are important for recognition by Ly49A by using a series of recombinant MHC class I molecules between H-2D d and K d (23). The important areas include ␤-sheet regions that form the bottom of ␣1/␣2 domain rather than ␣ helices of ␣1/␣2 domains, which form the functional binding site for Ly49A by the crystal structure data and our more recent mutagenesis data (28).…”

mentioning

confidence: 98%

“…Ly49A has a functional C-type lectin domain that can bind the polyanionic carbohydrate, fucoidan (26). However, Ly49A can recognize the H-2D d that lacks carbohydrate moiety (23). Recently, Tormo et al reported the crystal structure of the Ly49A/H-2D d complex (27), providing firm evidence for specific interaction of Ly49A with H-2D d .…”

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confidence: 99%

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The NK Cell MHC Class I Receptor Ly49A Detects Mutations on H-2Dd Inside and Outside of the Peptide Binding Groove

Matsumoto

Yokoyama

Kojima

et al. 2001

The Journal of Immunology

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N atural killer cells are a group of lymphocytes that spontaneously lyse certain tumor targets (1). The finding that cell lines defective for MHC class I expression were efficiently lysed by NK cells led to the missing self hypothesis: NK cells kill cells that lack normal expression of MHC class I molecules (2). Recent studies have established that NK cells express inhibitory receptors for MHC class I molecules (3, 4). The receptors can be classified into two groups by their structural characteristics. One group that includes human killer cell Ig-like receptors is characterized by two or three Ig-like domains in the extracellular region and configuration of type I transmembrane proteins (5, 6). NK cell MHC class I receptors of Ig-type have thus far been found only in primates, but not in rodents. gp49B1, which belongs to the Ig superfamily, is expressed on mouse NK cells (7,8); however, the ligand for gp49B1 may not be MHC class I. Another group of NK cell MHC class I receptors is characterized by disulfide-linked dimer of type II transmembrane protein with an extracellular region homologous to carbohydrate recognition domain of C-type lectin. This group includes the Ly49 family in mice (9 -12) and rats (13) and CD94/NKG2 heterodimer found in humans (14) and rodents (15, 16).The inhibitory receptors of both groups have one or two immune receptor tyrosine-based inhibitory motifs (ITIM) 3 characterized by an IXYXXL sequence in the cytoplasmic region (17). Upon ligand recognition, the Tyr residue in the ITIM is phosphorylated and recruits the Src homology domain-containing protein tyrosine phosphatase 1 with Src homology 2 domains. The recruited Src homology domain-containing protein tyrosine phosphatase 1 is believed to dephosphorylate unknown critical substrates to shut down positive signaling. There are activating type of MHC class I receptors of C-type lectin and Ig-type with extracellular domains similar to those of the inhibitory receptors. Instead of cytoplasmic ITIM, the activating receptors have characteristic charged amino acid residues in the transmembrane region, and by that associate with DAP12, an adapter component with cytoplasmic immune receptor tyrosine-based activating motif (18). Engagement of such receptors initiates an activation signaling cascade analogous to T or B cell receptor signaling.Mouse NK cells express the Ly49 family of receptors, which includes Ͼ10 members (9 -12, 19). Several lines of evidence demonstrate that Ly49A, a primary member of Ly49 family, is an inhibitory receptor that specifically recognizes a conformational epitope on H- The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

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Section: Cellsmentioning

confidence: 99%

Section: Site-directed Mutagenesismentioning

confidence: 99%

mentioning

confidence: 97%

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confidence: 98%

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confidence: 99%

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The NK Cell MHC Class I Receptor Ly49A Detects Mutations on H-2Dd Inside and Outside of the Peptide Binding Groove

Matsumoto

Yokoyama

Kojima

et al. 2001

The Journal of Immunology

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Impaired MHC class I (H-2Dd)-mediated protection against Ly-49A+ NK cells after amino acid substitutions in the antigen binding cleft

et al. 1998

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The MHC class I molecule H-2Dd (Dd) acts as a ligand for the inhibitory NK cell receptor Ly-49A. We have constructed altered Dd molecules by site-directed mutagenesis, replacing residues with the corresponding amino acids from the Db molecule, which fails to inhibit via Ly-49A. Mutations at positions 73 and 156 (DdS73WD156Y) impaired the protective effect of the Dd molecule, as evaluated by testing lymphoma cells transfected with the mutant gene for sensitivity to killing by Ly-49A+ NK cells in vitro and rejection by NK cells in vivo. The altered residues form a hydrophobic ridge across the floor of the antigen binding cleft. A mutation in the alpha helix of the alpha2 domain, facing the solvent and without direct contact with the peptide (DdA150S) had no effect. Dd recognition by Ly-49A+ NK cells is considered to be peptide dependent, but not peptide specific. Our results indicate that alterations of residues buried in the antigen binding cleft can induce changes in peptide binding patterns and/or conformational changes in the Dd molecule that make the trimolecular complex less permissive for inhibition of Ly-49A+ NK cells.

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α1 / α2 domains of H-2Dd, but not H-2Ld, induce “missing self” reactivityin vivo – No effect of H-2Ld on protection against NK cells expressing the inhibitory receptor Ly49G2

et al. 1998

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Introduction of the MHC class I transgene H-2D d on C57BL/6 (B6) background conveys NK cell-mediated "missing self" reactivity against transgene-negative cells, and down-regulates expression of the inhibitory receptors Ly49A and Ly49G2 in NK cells. We here present an analysis of transgenic mice expressing chimeric H-2D d /L d MHC class I transgenes, and show that the § 1/ § 2 domains of H-2D d were necessary and sufficient to induce "missing self" recognition and to down-modulate Ly49A and Ly49G2 receptors. In contrast, trans-genes containing the § 1/ § 2 domains of H-2L d induced none of these changes, suggesting that not all MHC class I alleles in a host necessarily take part in NK cell education. The lack of effect of the § 1/ § 2 domains of H-2L d on NK cell specificity was surprising, considering that both H-2L d and H-2D d have been reported to interact with Ly49G2. Therefore, the role of H-2L d for protection against NK cells expressing Ly49G2 was re-investigated in a transfec-tion system. In contradiction to earlier reports, we show that H-2D d , but not H-2L d , abolished killing by sorted Ly49G2 + NK cells, indicating that H-2L d does not inhibit NK cells via the Ly49G2 receptor.

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The Lectin-Like NK Cell Receptor Ly-49A Recognizes a Carbohydrate-Independent Epitope on Its MHC Class I Ligand

Cited by 70 publications

References 50 publications

The NK Cell MHC Class I Receptor Ly49A Detects Mutations on H-2Dd Inside and Outside of the Peptide Binding Groove

The NK Cell MHC Class I Receptor Ly49A Detects Mutations on H-2Dd Inside and Outside of the Peptide Binding Groove

Impaired MHC class I (H-2Dd)-mediated protection against Ly-49A+ NK cells after amino acid substitutions in the antigen binding cleft

α1 / α2 domains of H-2Dd, but not H-2Ld, induce “missing self” reactivityin vivo – No effect of H-2Ld on protection against NK cells expressing the inhibitory receptor Ly49G2

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