DC-SIGN Mediates Binding of Dendritic Cells to Authentic Pseudo-LewisY Glycolipids of Schistosoma mansoni Cercariae, the First Parasite-specific Ligand of DC-SIGN

Abstract

During schistosomiasis, parasite-derived glycoconjugates play a key role in manipulation of the host immune response, associated with persistence of the parasite. Among the candidate host receptors that are triggered by glycoconjugates are C-type lectins (CLRs) on dendritic cells (DCs), which in concerted action with Toll-like receptors determine the balance in DCs between induction of immunity versus tolerance. Here we report that the CLR DC-SIGN mediates adhesion of DCs to authentic glycolipids derived from Schistosoma mansoni cercariae and their excretory/secretory products. Structural characterization of the glycolipids, in combination with solid phase and cellular binding studies revealed that DC-SIGN binds to the carbohydrate moieties of both glycosphingolipid species with Galβ1–4(Fucα1–3)GlcNAc (LewisX) and Fucα1–3Galβ1–4(Fucα1–3)GlcNAc (pseudo-LewisY) determinants. Importantly, these data indicate that surveying DCs in the skin may encounter schistosome-derived glycolipids immediately after infection. Recent of of the carbohydrate binding of DC-SIGN to the of DC-SIGN to we that the binding of the to DC-SIGN with the the the of the of in the binding of DC-SIGN which in a of with the of the of that mansoni may the in the binding of DC-SIGN to which may to immune During schistosomiasis, parasite-derived glycoconjugates play a key role in manipulation of the host immune response, associated with persistence of the parasite. Among the candidate host receptors that are triggered by glycoconjugates are C-type lectins (CLRs) on dendritic cells (DCs), which in concerted action with Toll-like receptors determine the balance in DCs between induction of immunity versus tolerance. Here we report that the CLR DC-SIGN mediates adhesion of DCs to authentic glycolipids derived from Schistosoma mansoni cercariae and their excretory/secretory products. Structural characterization of the glycolipids, in combination with solid phase and cellular binding studies revealed that DC-SIGN binds to the carbohydrate moieties of both glycosphingolipid species with Galβ1–4(Fucα1–3)GlcNAc (LewisX) and Fucα1–3Galβ1–4(Fucα1–3)GlcNAc (pseudo-LewisY) determinants. Importantly, these data indicate that surveying DCs in the skin may encounter schistosome-derived glycolipids immediately after infection. Recent of of the carbohydrate binding of DC-SIGN to the of DC-SIGN to we that the binding of the to DC-SIGN with the the the of the of in the binding of DC-SIGN which in a of with the of the of that mansoni may the in the binding of DC-SIGN to which may to immune a by of the Schistosoma that of the of that the are in and of the host immune response, to their and in host a both a and a cercariae by the the host the skin and to the and to that and that host are the of a that and the which a of the immune with of associated with and the of host immune which cellular receptors are glycoconjugates and are to play in host which may by the glycoconjugates are that are of both and in the and of carbohydrate on these glycolipids by in the the a that from that in the to in by of a to the and a of of which are and of adhesion dendritic of adhesion dendritic and Galβ1–4(Fucα1–3)GlcNAc indicate in in glycoconjugates of of and and glycolipids glycoconjugates are to of from which and and to the of by cells from a induction of a of by cells of the immune by receptors on dendritic cells are in the of Toll-like receptors that and C-type lectins (CLRs) that to DCs on their and studies that of DCs that the and DCs to cells DCs a of that in a carbohydrate to play a role in the of the of to to and immunity are that the balance between and may the immune immune tolerance. of by lectins may immune in a of are immune a to the of the role of and in with their we to the receptors on cells that the we that the C-type DC-SIGN binds to Schistosoma mansoni the DC-SIGN a CLR that and on DCs DC-SIGN glycoconjugates and and with binding of to by the of and of in the of DC-SIGN we that the in DC-SIGN binding the of the and we that DC-SIGN binds to authentic of to Structural characterization of the moieties of the glycosphingolipid species revealed that a of the by we that DC-SIGN binds to glycosphingolipid species a with a that and from cells by a in the of and and the of the DCs by DCs of and and and of and of cells DC-SIGN by a of the of DC-SIGN the to a the both from from mansoni cercariae and by of of mansoni excretory/secretory by and glycolipids by and glycolipids by and a of a from by in to by by a with and of and from the from and glycolipids by with from moieties by and and from species by on a a from with to and to with to and a of by and of by to by and glycolipids in on and to the glycolipids to the with and with a and on and by with to the binding and on with a and a and in the in with mansoni and glycolipids, and with with in the of cells by cells and on a are the of adhesion of of Schistosoma mansoni cercariae from mansoni by the by cercariae to of the and the the of the of DC-SIGN with the from the to with the and the that play role in of to the the the and the a of and the by on of the of to the with the of the the with of the and the of in the binding in the the a of of mansoni by their binding to authentic glycolipids from mansoni and by and by glycolipids, and with a to the binding of DC-SIGN the of the of the in revealed that binds and the a binding to of glycolipids and that by DC-SIGN by the carbohydrate and of the of the and of the of the species that glycolipids by with studies a of glycolipids of the of the species of and and species with the a of and which the of glycolipids with and carbohydrate on studies on the of glycolipids the of to species with of and which by the of the after glycolipids to and the by their to DC-SIGN revealed that DC-SIGN glycolipids that in species with carbohydrate of by that a of glycolipids moieties of the a determine which of these moieties are by we to carbohydrate moieties that from the of glycolipids from mansoni are to and of in a glycolipids with and carbohydrate moieties species with of and of by of from of mansoni cercariae and by in a of DC-SIGN to glycolipids of mansoni of DC-SIGN to mansoni glycolipids by species in are by glycolipids and by of and and are of the of from glycolipids by from by and by with the in the of glycolipids the the of with with the of a a with the of to a by the species to to and to by in and of from glycolipids by with and by of and are are in and of with of the and and the are by of the and are by to from by the of of to and of and by of the by that the with the of of a with a of to the of the and and in with the of a of to the by a the of the with the of in to a of the and and the to the and revealed a of the and of DC-SIGN to and and by to by to a of in with the of the and the of that and the of by a with of and by with to their carbohydrate to the of of in binding of to and by revealed of the by with the a the in to a carbohydrate DC-SIGN binds authentic glycolipids and we a cellular adhesion cells with DC-SIGN of DC-SIGN on their by glycolipids binding to with to the binding of cellular DC-SIGN to glycolipids and binding by a DC-SIGN and DC-SIGN on their glycolipids and the are by DC-SIGN on the that on their adhesion by the a DC-SIGN that binding of the cells to the glycolipids the of these studies that DC-SIGN mediates the binding of to authentic carbohydrate by mansoni of and of and and binds to and of to in of of and of to of to by of are on on dendritic cells with authentic mansoni glycolipids and and of DC-SIGN on and by of DC-SIGN on to glycolipids and by adhesion in the of a to DC-SIGN are of in of of in the DC-SIGN binding on the of the DC-SIGN with of by and of the binding of the with the to the in with of that the to and of DC-SIGN with and of the of DC-SIGN with and are by the with the from by a in of the of in a with the of a both and the of in from the in the of DC-SIGN with a of the of with the of between and are in of the a with DC-SIGN with with a a in to a in a mansoni with and to the that to to DC-SIGN in are in a that with DCs in DCs are to encounter a of and glycolipids that the cercariae to determine the and are glycolipids from in from with the by revealed that glycolipids species with and with a of of which in the the of DC-SIGN with mansoni glycolipids to derived from of mansoni cercariae are by both and dendritic Structural characterization of the glycolipids revealed that DC-SIGN binds species and species to that in both and that may are the DC-SIGN in studies to the of the between DC-SIGN and glycolipids in host that glycolipids with DC-SIGN in with studies that species with are in a of the of DC-SIGN to of of the of DC-SIGN to the that the and of the with in the binding the to which with the the the in a binding the that in DC-SIGN to the binding and a with and of in combination with binding studies of and of DC-SIGN and we the binding of in DC-SIGN that a on the of a with the of which with the of binding studies that that of binding in the studies we binding of cellular to that a to a on of the to the of the of a that in a with the of the that the binding of DC-SIGN to the of the of to and that mansoni may to a in the of in the of binding of the of in with and a that the of the of the which by a of the to that in the with DCs and are the immune cells that encounter and are in the and of and immune a of and studies indicate that glycolipids are to the immune of moieties of in that glycolipids of and in and of the the that the of cells with on of a which the of we report that DCs with authentic and the CLR that DCs may with in infection. the host in the and these cercariae after of the skin by their and of products. of the glycolipids derived from that species with and determinants. that the are candidate to by surveying the DC-SIGN which are in the that DCs and which are on that which with and may in a are that DC-SIGN to immune glycoconjugates that are by DC-SIGN to immune to immune to immune to in their DC-SIGN a role in of the of to the of the in the to cells in the host a immune response, that these to the host immune a and a immune response, which associated with persistence of the data that DC-SIGN the glycolipids, glycolipids a that glycolipids and may a that a to the of of that may to the host immune by in of infection. DC-SIGN to and play a role in of these glycoconjugates and schistosomiasis, to the role of DCs in both the immune that in the immune and that are by the a by of the Schistosoma that of the of that the are in and of the host immune response, to their and in host a both a and a cercariae by the the host the skin and to the and to that and that host are the of a that and the which a of During the immune with of associated with and the of host immune which cellular receptors are glycoconjugates and are to play in host which may by the glycoconjugates are that are of both and in the and of carbohydrate on these glycolipids by in the the a that from that in the to in by of a to the and a of of which are and of adhesion dendritic of adhesion dendritic and Galβ1–4(Fucα1–3)GlcNAc dendritic C-type of carbohydrate dendritic excretory/secretory adhesion dendritic Galβ1–4(Fucα1–3)GlcNAc Fucα1–3Galβ1–4(Fucα1–3)GlcNAc dendritic C-type of carbohydrate dendritic excretory/secretory adhesion dendritic Galβ1–4(Fucα1–3)GlcNAc Fucα1–3Galβ1–4(Fucα1–3)GlcNAc indicate in in glycoconjugates of of and and glycolipids glycoconjugates are to of from which and and to the of by cells from a induction of a of by cells of the immune by receptors on dendritic cells are in the of Toll-like receptors that and C-type lectins (CLRs) that to DCs on their and studies that of DCs that the and DCs to cells DCs a of that in a carbohydrate to play a role in the of the of to to and immunity are that the balance between and may the immune immune tolerance. of by lectins may immune in a of are immune a to the of the role of and in with their we to the receptors on cells that the we that the C-type DC-SIGN binds to Schistosoma mansoni the DC-SIGN a CLR that and on DCs DC-SIGN glycoconjugates and and with binding of to by the of and of in the of DC-SIGN we that the in DC-SIGN binding the of the and we that DC-SIGN binds to authentic of to Structural characterization of the moieties of the glycosphingolipid species revealed that a of the by we that DC-SIGN binds to glycosphingolipid species a with a that and from cells by a in the of and and the of the DCs by DCs of and and and of and of cells DC-SIGN by a of the of DC-SIGN the to a the both from from mansoni cercariae and by of of mansoni excretory/secretory by and glycolipids by and glycolipids by and a of a from by in to by by a with and of and from the from and glycolipids by with from moieties by and and from species by on a a from with to and to with to and a of by and of by to by and glycolipids in on and to the glycolipids to the with and with a and on and by with to the binding and on with a and a and in the in with mansoni and glycolipids, and with with in the of cells by cells and on a are the of adhesion of of Schistosoma mansoni cercariae from mansoni by the by cercariae to of the and the the of the of DC-SIGN with the from the to with the and the that play role in of to the the the and the a of and the by on of the of to the with the of the the with of the and the of in the binding in the the a of and from cells by a in the of and and the of the DCs by DCs of and and and of and of cells DC-SIGN by a of the of DC-SIGN the to a the both from from mansoni cercariae and by of of mansoni excretory/secretory by and glycolipids by and glycolipids by and a of a from by in to by by a with and of and from the from and glycolipids by with from moieties by and and from species by on a a from with to and to with to and a of by and of by to by and glycolipids in on and to the glycolipids to the with and with a and on and by with to the binding and on with a and a and in the in with mansoni and glycolipids, and with with in the of cells by cells and on a are the of adhesion of of Schistosoma mansoni cercariae from mansoni by the by cercariae to of the and the the of the of DC-SIGN with the from the to with the and the that play role in of to the the the and the a of and the by on of the of to the with the of the the with of the and the of in the binding in the the a of of mansoni by their binding to authentic glycolipids from mansoni and by and by glycolipids, and with a to the binding of DC-SIGN the of the of the in revealed that binds and the a binding to of glycolipids and that by DC-SIGN by the carbohydrate and of the of the and of the of the species that glycolipids by with studies a of glycolipids of the of the species of and and species with the a of and which the of glycolipids with and carbohydrate on studies on the of glycolipids the of to species with of and which by the of the after glycolipids to and the by their to DC-SIGN revealed that DC-SIGN glycolipids that in species with carbohydrate of by that a of glycolipids moieties of the a determine which of these moieties are by we to carbohydrate moieties that from the of from of mansoni cercariae and by in a of DC-SIGN to glycolipids of mansoni of DC-SIGN to mansoni glycolipids by species in are by glycolipids and by of and and are of the of from glycolipids by from by and by with the in the of glycolipids the the of with with the of a a with the of to a by the species to to and to by in and of from glycolipids by with and by of and are are in and of with of the and and the are by of the and are by to from by the of of to and of and by of the by that the with the of of a with a of to the of the and and in with the of a of to the by a the of the with the of in to a of the and and the to the and revealed a of the and of DC-SIGN to and and by to by to a of in with the of the and the of that and the of by a with of and by with to their carbohydrate to the of of in binding of to and by revealed of the by with the a the in to a carbohydrate DC-SIGN binds authentic glycolipids and we a cellular adhesion cells with DC-SIGN of DC-SIGN on their by glycolipids binding to with to the binding of cellular DC-SIGN to glycolipids and binding by a DC-SIGN and DC-SIGN on their glycolipids and the are by DC-SIGN on the that on their adhesion by the a DC-SIGN that binding of the cells to the glycolipids the of these studies that DC-SIGN mediates the binding of to authentic carbohydrate by mansoni of and of and and binds to and of to in of of and of to of to by of are on on dendritic cells with authentic mansoni glycolipids and and of DC-SIGN on and by of DC-SIGN on to glycolipids and by adhesion in the of a to DC-SIGN are of in of of in the DC-SIGN binding on the of the DC-SIGN with of by and of the binding of the with the to the in with of that the to and of DC-SIGN with and of the of DC-SIGN with and are by the with the from by a in of the of in a with the of a both and the of in from the in the of DC-SIGN with a of the of with the of between and are in of the a with DC-SIGN with with a a in to a in a mansoni with and to the that to to DC-SIGN in are in a that with DCs in DCs are to encounter a of and glycolipids that the cercariae to determine the and are glycolipids from in from with the by revealed that glycolipids species with and with a of of which in the of mansoni by their binding to authentic glycolipids from mansoni and by and by glycolipids, and with a to the binding of DC-SIGN the of the of the in revealed that binds and the a binding to of glycolipids and that by DC-SIGN by the carbohydrate and of the of the and of the of the species that glycolipids by with studies a of glycolipids of the of the species of and and species with the a of and which the of glycolipids with and carbohydrate on studies on the of glycolipids the of to species with of and which by the of the after glycolipids to and the by their to DC-SIGN revealed that DC-SIGN glycolipids that in species with carbohydrate of by that a of glycolipids moieties of the a determine which of these moieties are by we to carbohydrate moieties that from the of the of from glycolipids by from by and by with the in the of glycolipids the the of with with the of a a with the of to a by the species to to and to by in and of and by of the by that the with the of of a with a of to the of the and and in with the of a of to the by a the of the with the of in to a of the and and the to the and revealed a of the and of DC-SIGN to and and by to by to a of in with the of the and the of that and the of by a with of and by with to their carbohydrate to the of of in binding of to and by revealed of the by with the a the in to a carbohydrate DC-SIGN binds authentic glycolipids and we a cellular adhesion cells with DC-SIGN of DC-SIGN on their by glycolipids binding to with to the binding of cellular DC-SIGN to glycolipids and binding by a DC-SIGN and DC-SIGN on their glycolipids and the are by DC-SIGN on the that on their adhesion by the a DC-SIGN that binding of the cells to the glycolipids the of these studies that DC-SIGN mediates the binding of to authentic carbohydrate by mansoni of of in the DC-SIGN binding on the of the DC-SIGN with of by and of the binding of the with the to the in with of that the to and from by a in of the of in a with the of a both and the of in from the in the of DC-SIGN with a of the of with the of between and are in of the a with DC-SIGN with with a a in to a in a mansoni with and to the that to to DC-SIGN in are in a that with DCs in DCs are to encounter a of and glycolipids that the cercariae to determine the and are glycolipids from in from with the by revealed that glycolipids species with and with a of of which in the the of DC-SIGN with mansoni glycolipids to derived from of mansoni cercariae are by both and dendritic Structural characterization of the glycolipids revealed that DC-SIGN binds species and species to that in both and that may are the DC-SIGN in studies to the of the between DC-SIGN and glycolipids in host that glycolipids with DC-SIGN in with studies that species with are in a of the of DC-SIGN to of of the of DC-SIGN to the that the and of the with in the binding the to which with the the the in a binding the that in DC-SIGN to the binding and a with and of in combination with binding studies of and of DC-SIGN and we the binding of in DC-SIGN that a on the of a with the of which with the of binding studies that that of binding in the studies we binding of cellular to that a to a on of the to the of the of a that in a with the of the that the binding of DC-SIGN to the of the of to and that mansoni may to a in the of in the of binding of the of in with and a that the of the of the which by a of the to that in the with DCs and are the immune cells that encounter and are in the and of and immune a of and studies indicate that glycolipids are to the immune of moieties of in that glycolipids of and in and of the the that the of cells with on of a which the of we report that DCs with authentic and the CLR that DCs may with in infection. the host in the and these cercariae after of the skin by their and of products. of the glycolipids derived from that species with and determinants. that the are candidate to by surveying the DC-SIGN which are in the that DCs and which are on that which with and may in a are that DC-SIGN to immune glycoconjugates that are by DC-SIGN to immune to immune to immune to in their DC-SIGN a role in of the of to the of the in the to cells in the host a immune response, that these to the host immune a and a immune response, which associated with persistence of the data that DC-SIGN the glycolipids, glycolipids a that glycolipids and may a that a to the of of that may to the host immune by in of infection. DC-SIGN to and play a role in of these glycoconjugates and schistosomiasis, to the role of DCs in both the immune that in the immune and that are by the the of DC-SIGN with mansoni glycolipids to derived from of mansoni cercariae are by both and dendritic Structural characterization of the glycolipids revealed that DC-SIGN binds species and species to that in both and that may are the DC-SIGN in studies to the of the between DC-SIGN and glycolipids in host that glycolipids with DC-SIGN in with studies that species with are in a of the of DC-SIGN to of of the of DC-SIGN to the that the and of the with in the binding the to which with the the the in a binding the that in DC-SIGN to the binding and a with and of in combination with binding studies of and of DC-SIGN and we the binding of in DC-SIGN that a on the of a with the of which with the of binding studies that that of binding in the studies we binding of cellular to that a to a on of the to the of the of a that in a with the of the that the binding of DC-SIGN to the of the of to and that mansoni may to a in the of in the of binding of the of in with and a that the of the of the which by a of the to that in the with DCs and are the immune cells that encounter and are in the and of and immune a of and studies indicate that glycolipids are to the immune of moieties of in that glycolipids of and in and of the the that the of cells with on of a which the of Here we report that DCs with authentic and the CLR that DCs may with in infection. the host in the and these cercariae after of the skin by their and of products. of the glycolipids derived from that species with and determinants. that the are candidate to by surveying the DC-SIGN which are in the that DCs and which are on that which with and may in a are that DC-SIGN to immune glycoconjugates that are by DC-SIGN to immune to immune to immune to in their DC-SIGN a role in of the of to the of the in the to cells in the host a immune response, that these to the host immune a and a immune response, which associated with persistence of the data that DC-SIGN the glycolipids, glycolipids a that glycolipids and may a that a to the of of that may to the host immune by in of infection. DC-SIGN to and play a role in of these glycoconjugates and schistosomiasis, to the role of DCs in both the immune that in the immune and that are by the of of mansoni cercariae and and mansoni products.