Stable masking by H-2D<sup>d</sup>cis ligand limits Ly49A relocalization to the site of NK cell/target cell contact

Back, Jonathan; Chalifour, Anick; Scarpellino, Léonardo; Held, Werner

doi:10.1073/pnas.0607418104

Cited by 49 publications

(65 citation statements)

References 33 publications

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“…Because SDS-PAGE analysis of dissolved crystals confirmed the presence of an intact stalk (data not shown), with no evidence of proteolysis, we concluded that the disorder in the crystal lattice indicates flexibility of the stalk, which secondary structure predictions suggest is a long coiled coil interspersed with flexible loops. This mobility is presumably required to permit binding of Ly49 receptors on the NK cell to MHC-I on an opposing target (trans interactions), as well as to MHC-I on the NK cell itself (cis interactions) (22)(23)(24).…”

Section: Resultsmentioning

confidence: 99%

“…For example, cell-cell adhesion assays using Ly49 and MHC-I transfectants, as well as direct binding assays using soluble recombinant proteins, may not detect low affinity interactions that are nevertheless biologically relevant. In addition, cis interactions between Ly49 and MHC-I molecules on the same NK cell may prevent trans interactions between these molecules on opposing cells (22)(23)(24). As a result, the MHC specificities of most Ly49s are unknown, or ambiguous at best (2, 3).…”

Section: Structure Of the Ly49c-h-2k Bmentioning

confidence: 99%

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Molecular Architecture of the Major Histocompatibility Complex Class I-binding Site of Ly49 Natural Killer Cell Receptors

Deng

Cho

Malchiodi

et al. 2008

Journal of Biological Chemistry

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The cytolytic activity of NK cells is regulated by a delicate balance of activating and inhibitory signals mediated through distinct classes of receptors found on their surface. The dominant signal received by an NK cell through its interaction with normal levels of major histocompatibility complex class I (MHC-I) molecules on target cells is inhibitory. If the level of MHC-I is reduced through tumorigenic or infectious processes, this inhibitory signal is attenuated, and the NK cell is activated (1-3). In this way, cells with abnormal MHC-I expression become targets of NK lytic activity.Several receptor families have been identified on primate and rodent NK cells that monitor MHC-I expression on surrounding cells (3-5). These include the killer immunoglobulin-like receptors, members of the Ly49 family (Ly49s), and the CD94-NKG2 family of receptors. Additionally, the activating receptor NKG2D recognizes MHC-like molecules, such as MICA, that are up-regulated in stressed tissues (6). The mouse Ly49 family includes at least 23 expressed or potential members (Ly49A-W), along with about 15 allelic variants (2, 7). These highly polymorphic receptors constitute the main MHC-monitoring molecules on rodent NK cells. Although most Ly49s inhibit NK cell-mediated cytolysis after binding to MHC-I ligands, some are activating. Ly49s recognize one or more H-2D or H-2K alleles, independently of the MHC-bound peptide (2, 3). Their binding properties range from the broad recognition of MHC-I molecules by Ly49C to the allelic specificity of Ly49A. Recently, crucial roles for Ly49 receptors in antiviral immunity have been discovered. In one case, the m157 gene product of mouse cytomegalovirus (MCMV) was shown to interact directly with an inhibitory Ly49 (Ly49I) in a susceptible mouse strain and with an activating Ly49 (Ly49H) in a resistant one (8, 9). In another case, the activating receptor Ly49P was found to confer resistance to MCMV by interacting with H-2D molecules on MCMV-infected cells (10).Ly49 receptors belong to the C-type lectin-like family of proteins, which also includes CD94-NKG2 and NKG2D (4, 5). Ly49s are homodimeric type II glycoproteins, with each chain composed of a C-type lectin-like domain, termed the natural killer receptor domain (NKD), connected by a stalk of ϳ70 residues to the transmembrane and cytoplasmic domains. Crystal structures have been reported for Ly49A bound to H-2D d (11) and for Ly49C bound to H-2K b (12). These structures showed that both Ly49s engage MHC-I at a broad cavity beneath the * This work was supported, in whole or in part, by National Institutes of Health Grant AI047990. 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. The atomic coordinates and structure factors (codes 3C8J, 3CAD, and 3C8K)

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Section: Resultsmentioning

confidence: 99%

Section: Structure Of the Ly49c-h-2k Bmentioning

confidence: 99%

Molecular Architecture of the Major Histocompatibility Complex Class I-binding Site of Ly49 Natural Killer Cell Receptors

Deng

Cho

Malchiodi

et al. 2008

Journal of Biological Chemistry

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“…A vast majority of Ly49C molecules are masked by H-2 K b molecules through interactions in cis on B6 WT NK cells, whereas on Ly49C-Tg NK cells, more Ly49C molecules are free because of the higher expression level of the receptor (data not shown). These molecules are able to interact with H-2 K b ligands expressed in trans and are also likely to have a greater mobility on the cell membrane, as reported (16,60). Therefore, it is possible that the extent of Ly49C receptors engaged through cis interactions plays a role in memory NK cell differentiation and/or persistence.…”

Section: Analysis Of Ly49cmentioning

confidence: 89%

Ly49C Impairs NK Cell Memory in Mouse Cytomegalovirus Infection

Forbes

Scalzo

Degli-Esposti

et al. 2016

The Journal of Immunology

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NK cells possess inhibitory receptors that are responsible for self-MHC class I recognition; beyond their inhibitory function, accumulating evidence indicates that such receptors confer NK cell functional competence through an unclear process termed “licensing.” Ly49C is the main self-specific inhibitory Ly49 receptor in H-2b C57BL/6 (B6) mice. We used B6 Ly49C-transgenic and B6 β2 microglobulin (β2m)-knockout Ly49C-transgenic mice to investigate the impact of licensing through this inhibitory receptor in precursor and mature NK cells. We found that self-specific inhibitory receptors affected NK cell precursor survival and proliferation at particular developmental stages in an MHC class I–dependent manner. The presence of Ly49C impacted the NK cell repertoire in a β2m-dependent manner, with reduced Ly49A+, Ly49G2+, and Ly49D+ subsets, an increased DNAM-1+ subset, and higher NKG2D expression. Licensed NK cells displayed a skewed distribution of the maturation stages, which was characterized by differential CD27 and CD11b expression, toward the mature phenotypes. We found that Ly49C-mediated licensing induced a split effect on NK cell functions, with increased cytokine-production capabilities following engagement of various activating receptors while cytotoxicity remained unchanged. Analysis of licensed NK cell functions in vivo, in a system of mouse CMV infection, indicated that licensing did not play a major role in the NK cell antiviral response during acute infection, but it strongly impaired the generation and/or persistence of memory NK cells. This study unravels multifaceted effects of licensing on NK cell populations and their functions.

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“…Cis and trans interactions have two distinct receptor conformations made possible due to the flexible stalk; the stalk is able to bend into a back-fold conformation allowing for trans binding and straightens into an extended conformation for cis interactions (18). Cis interactions are stable and sequester Ly49A so that most receptors are not available for MHC-I binding in trans (19). The end result is that the NK cell is more sensitive to small changes in MHC-I levels on target cells and ultimately lowers the activation threshold (17).…”

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confidence: 99%

Optimized Tetramer Analysis Reveals Ly49 Promiscuity for MHC Ligands

McFall

Al-Khattabi

et al. 2013

The Journal of Immunology

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Murine Ly49 receptors, which are expressed mainly on NK and NKT cells, interact with MHC class I (MHC-I) molecules with varying specificity. Differing reports of Ly49/MHC binding affinities may be affected by multiple factors, including cis versus trans competition and species origin of the MHC-I L chain (β2-microglobulin). To determine the contribution of each of these factors, Ly49G, Ly49I, Ly49O, Ly49V, and Ly49Q receptors from the 129 mouse strain were expressed individually on human 293T cells or the mouse cell lines MHC-I–deficient C1498, H-2b–expressing MC57G, and H-2k–expressing L929. The capacity to bind to H-2Db– and H-2Kb–soluble MHC-I tetramers containing either human or murine β2-microglobulin L chains was tested for all five Ly49 receptors in all four cell lines. We found that most of these five inhibitory Ly49 receptors show binding for one or both self–MHC-I molecules in soluble tetramer binding assays when three conditions are fulfilled: 1) lack of competing cis interactions, 2) tetramer L chain is of mouse origin, and 3) Ly49 is expressed in mouse and not human cell lines. Furthermore, Ly49Q, the single known MHC-I receptor on plasmacytoid dendritic cells, was shown to bind H-2Db in addition to H-2Kb when the above conditions were met, suggesting that Ly49Q functions as a pan–MHC-Ia receptor on plasmacytoid dendritic cells. In this study, we have optimized the parameters for soluble tetramer binding analyses to enhance future Ly49 ligand identification and to better evaluate specific contributions by different Ly49/MHC-I pairs to NK cell education and function.

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Stable masking by H-2D^dcis ligand limits Ly49A relocalization to the site of NK cell/target cell contact

Cited by 49 publications

References 33 publications

Molecular Architecture of the Major Histocompatibility Complex Class I-binding Site of Ly49 Natural Killer Cell Receptors

Molecular Architecture of the Major Histocompatibility Complex Class I-binding Site of Ly49 Natural Killer Cell Receptors

Ly49C Impairs NK Cell Memory in Mouse Cytomegalovirus Infection

Optimized Tetramer Analysis Reveals Ly49 Promiscuity for MHC Ligands

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Stable masking by H-2Ddcis ligand limits Ly49A relocalization to the site of NK cell/target cell contact

Cited by 49 publications

References 33 publications

Molecular Architecture of the Major Histocompatibility Complex Class I-binding Site of Ly49 Natural Killer Cell Receptors

Molecular Architecture of the Major Histocompatibility Complex Class I-binding Site of Ly49 Natural Killer Cell Receptors

Ly49C Impairs NK Cell Memory in Mouse Cytomegalovirus Infection

Optimized Tetramer Analysis Reveals Ly49 Promiscuity for MHC Ligands

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Stable masking by H-2D^dcis ligand limits Ly49A relocalization to the site of NK cell/target cell contact