N‐linked oligosaccharides can protect target cells from the lysis mediated by NK cells but not by cytotoxic T lymphocytes: role of NKG2‐A

Abstract

We have previously shown that glycophorin A (GPA), inserted by electropulsation into the membrane of K562 cells, protected them from natural killer (NK) cell-mediated cytotoxicity and the unique N-linked oligosaccharide of GPA was essential for resistance to occur. The present study demonstrates that the protection level conferred by GPA is similar to the resistance induced by HLA-Cw3 expressed by transfected K562 cells. A monoclonal antibody against NKG2-A, an NK inhibitory receptor interacting with HLA class I antigens and belonging to the C-type lectin receptor, was able to restore the ability of NK cells to lyse K562 cells expressing HLA-Cw3 at the cell membrane but not electroinserted-GPA, suggesting that the N-linked oligosaccharide of GPA cannot be a ligand for NKG2-A. GPA was then electroinserted into the membrane of two lymphoblastoid B-cell lines: one was sensitive to NK cell-mediated lysis, the other was susceptible to cytotoxic CD8+ T-lymphocyte (CTL)-mediated cytotoxicity. The electroinserted GPA protected the target cells from NK-mediated cytotoxicity, whereas it did not modify the cell susceptibility to lysis by CTL. Endoglycosidase F treatment abolished the resistance towards NK cell-mediated lysis, suggesting that N-linked glycans could inhibit mechanisms used by NK cells to exert their cytotoxic function in agreement with our previous results.

Clustered carbohydrates as a target for natural killer cells: a model system

“…The main features of the glycosynapse are speciWcity, high variability of eVect depending on clustering that directs proper orientation of "glycotopes", and a synergistic eVect with protein-dependent interactions (Hakomori 2004). Previously it was shown that complex substances with clustered saccharide presentation can aVect NK cell recognition and activation (Ogata et al 1992;Duan et al 1994;El Ouagari et al 1995;Sol et al 1999), in compliance with these requirements. Our results with polymeric glycoconjugates are also consistent with this proposed model of saccharide interaction.…”

“…More recently, the inhibitory receptor siglec-7 expressed on NK cells was found to recognize speciWcally Sia2-8Sia motif (Nicoll et al 2003). Interestingly, N-linked but not O-linked carbohydrate chains modulated NK cell cytotoxic activity, and the eVect of the N-linked saccharide chains was also shown to depend on their structure (Yoshimura et al 1996;Sol et al 1999;Baba et al 2000). In particular, the complex N-linked carbohydrate chain glycans of glycophorin A increased cell resistance to NK cell killing (El Ouagari et al 1995) whereas high mannose-type glycans enhanced target cell sensitivity to natural killing (Ahrens 1993).…”

“…Cell surface oligosaccharides are strongly implicated in the regulation of NK cell eVector functions, positive and negative eVects of saccharides on NK-cell-mediated cytotoxicity have been demonstrated in several experimental models (Ogata et al 1992;Yoshimura et al 1996;Sol et al 1999). Some of earliest data on the inhibition of NK cell cytolytic function were obtained using substances containing or consisting of various saccharides capable of binding to NK cells, including sialo-oligosaccharides, glycosphingolipids, -glucans and others (Van Rinsum et al 1986;Bergelson et al 1989;Duan et al 1994;Inverardi et al 1997).…”

Stress-Induced Molecules in Regulation of NK Cell Activity

“…Membraneassociated glycans by their structural diversity might provide fine tuning of NK cell -target cell interactions and regulate NK cell activity. Positive and negative effects of various carbohydrate compounds including sialo-oligosaccharides, glycosphingolipids, complex and high mannose-type N-glycans, and others on NK cell-mediated effector functions have also been reported [31][32][33]. However only in rare cases ligand-receptor signaling pathways underlying the saccharide effects were identified.…”

Thomsen‐Friedenreich (T) antigen expression increases sensitivity of natural killer cell lysis of cancer cells

“…These inhibitory receptors are fairly well studied, but the activating receptors remain poorly characterized. The best studied among them are the Fc receptor for IgG (CD16) and, in mice, NKR‐P1 and, in humans, NKp44 and NKp46 8. The problem with the characterization of these receptors is that most of them have, as of yet, unknown ligands.…”