Ganglioside GD3 expression on target cells can modulate NK cell cytotoxicity via siglec‐7‐dependent and ‐independent mechanisms

Abstract

Siglec-7 is a sialic acid binding receptor with inhibitory potential, expressed on human NK cells and monocytes. It has an unusual binding preference for § 2,8-linked disialic acids, such as those displayed by ganglioside GD3. Here we have investigated whether siglec-7-GD3 interactions are able to modulate NK cell cytotoxicity. Using synthetic polyacrylamide glycoprobes, siglec-7 was found to be masked at the NK cell surface but it could be unmasked by sialidase treatment of NK cells. GD3 synthase-transfected P815 target cells expressed high levels of GD3 and bound strongly to recombinant siglec-7-Fc protein. Surprisingly, GD3 synthase-transfected P815 cells were killed more effectively by untreated cells in a siglec-7-independent manner. However, following sialidase treatment of NK cells, a siglec-7-dependent inhibition of killing was observed. These findings have important implications for NK cell cytotoxicity against tumor cells like melanoma that express high levels of GD3 ganglioside.

The murine inhibitory receptor mSiglec‐E is expressed broadly on cells of the innate immune system whereas mSiglec‐F is restricted to eosinophils

“…Although mSiglec-E does not exhibit any significant sequence similarity with hSiglec-7 in the C-C' loop, it possesses a cluster of three basic residues that could favor charge interactions with disialic acids (C-C' loop: TDRRKD). Recent studies in our laboratory have demonstrated that overexpressed GD3 (a ganglioside carrying § 2,8-linked disialic acid) on target cells binds to hSiglec-7 on human NK cells and contributes to the down-regulation of target cell killing [29]. Whether sialic acid engagement of mSiglec-E expressed on NK cells and monocytes is able to similarly modulate cellular function awaits future studies.…”

Siglec-7 Undergoes a Major Conformational Change When Complexed with the α(2,8)-Disialylganglioside GT1b

“…Cytotoxicity assays have shown that an interaction between Siglec-7, expressed on NK cells, and GD3, expressed on target cells, can down-modulate NK killing (21). It is speculated that Siglec-7 may perform a protective role, recognizing such ligands as markers of "self " and preventing inappropriate NK activation.…”

“…Siglec-7 is an inhibitory receptor expressed on NK cells and to a lesser extent, monocytes and a subset of CD8ϩ T cells (13,(17)(18)(19)(20)(21). In vitro binding studies have revealed that Siglec-7 shows a marked preference for glycoconjugates bearing ␣(2,8)-linked disialic acid and branched ␣(2,6)-linked sialic acid (22).…”

“…The ␣(2,8)-linked disialic acid moiety is present in b-series gangliosides (and other gangliosides such as GT1a and GD1c). Importantly, Nicoll et al (21), have demonstrated that a b-series ganglioside, GD3, 3 when expressed on target cells, was able to mediate interactions with Siglec-7 expressed on NK cells, leading to the suppression of NK mediated cytolytic activity. This disialyl motif has also been identified on the serum glycoproteins fetuin, ␣2-macrogobulin, and adipo Q (23), neural cell adhesion molecule in the central nervous system (24), and a 70-kDa glycoprotein found on T cells (25).…”

Apoptotic modification of glycosphingolipids of human granulocytes

“…сіалозв'язуючий лектин І типу сіглек 7 [2], беруть участь у регенерації мієлінового шару, взаємодіючи через мієлін асоційований глікопротеїн [1,3], можуть регулюва-ти активність рецепторів інсуліну та ЕФР, взаємодіючи із тирозинкіназними доме-нами [3,4], є лігандами, що розпізнаються різними токсинами прокаріот, а також можуть брати участь у розпізнаванні клітин макрофагами. Біосинтез гангліозидів [5], який у спрощеному вигляді представлено на рис.1, сприяє різноманітності мож-ливих гліканових ланцюгів цих молекул.…”