Major histocompatibility complex class II association and induction of T cell responses by carbohydrates and glycopeptides

Ishioka, Glenn; Lamont, Alan; Thomson, David; Bulbow, Nancy; Gaeta, F. C. A.; Sette, Alessandro; Grey, Howard M.

doi:10.1007/bf00201108

Cited by 25 publications

(29 citation statements)

References 23 publications

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“…The absence of this enzyme in humans results in Fabry's disease (24). Moreover, carbohydrate chains are incapable of binding to class II MHC molecules (25). These considerations are in accord with our observations on the absence of in vitro proliferative response of T cells to α-gal epitopes ( Figure 5).…”

Section: Discussionsupporting

confidence: 91%

Differential immune responses to α-gal epitopes on xenografts and allografts: implications for accommodation in xenotransplantation

Tanemura¹,

Yin²,

Chong³

et al. 2000

J. Clin. Invest.

152

175

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Section: Discussionsupporting

confidence: 91%

Differential immune responses to α-gal epitopes on xenografts and allografts: implications for accommodation in xenotransplantation

Tanemura¹,

Yin²,

Chong³

et al. 2000

J. Clin. Invest.

152

175

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“…On the other hand, if GalNAc is pointed toward the MHC molecule and if it is unable to accommodate in the MHC groove, it can prevent effective binding of the glycopeptide to MHC, being unable to mount a T cell response (62). N-Glycosylated peptides have also been shown to greatly reduce binding to MHC (63). In the present study, both T cell hybridomas and in vivo MUC6-primed T cells recognized the MUC6:Tn glycoproteins, suggesting that GalNAc residues may be placed outside the TCR binding region, as seen for T cells generated to glycopeptides with high immunogenicity that cross-reacted with the non-glycosylated peptide (63).…”

Section: Discussionsupporting

confidence: 58%

“…N-Glycosylated peptides have also been shown to greatly reduce binding to MHC (63). In the present study, both T cell hybridomas and in vivo MUC6-primed T cells recognized the MUC6:Tn glycoproteins, suggesting that GalNAc residues may be placed outside the TCR binding region, as seen for T cells generated to glycopeptides with high immunogenicity that cross-reacted with the non-glycosylated peptide (63). T cell hybridomas generated to the non-glycosylated peptide reacted equally well, toward the amino-terminal substituted glycopeptides (64).…”

Section: Discussionmentioning

confidence: 99%

Tn Glycosylation of the MUC6 Protein Modulates Its Immunogenicity and Promotes the Induction of Th17-biased T Cell Responses

Freire

Lo‐Man

Bay

et al. 2011

Journal of Biological Chemistry

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The Tn antigen (␣-GalNAc-O-Ser/Thr) is one of the most specific human cancer-associated structures. This antigen, together with mucins, the major carriers of O-glycosylated tumor antigens in adenocarcinomas, are being evaluated as anticancer immunotherapeutic targets. In particular, the MUC6 protein, which is normally expressed only in gastric tissues, has been detected in intestinal, pulmonary, colorectal, and breast carcinomas. To develop anti-cancer vaccines based on the Tn antigen, we produced MUC6 proteins with different Tn density by using mixtures of recombinant ppGalNAc-T1, -T2, and -T7. The obtained glycoproteins were characterized and analyzed for their immunological properties, as compared with the non-glycosylated MUC6. We show that these various MUC6:Tn glycoproteins were well recognized by both MUC6 and Tn-specific antibodies. However, Tn glycosylation of the MUC6 protein strongly affected their immunogenicity by partially abrogating Th1 cell responses, and promoting IL-17 responses. Moreover, the non-glycosylated MUC6 was more efficiently presented than MUC6:Tn glycoproteins to specific T CD4 ؉ hybridomas, suggesting that Tn glycosylation may affect MUC6 processing or MHC binding of the processed peptides. In conclusion, our results indicate that Tn glycosylation of the MUC6 protein strongly affects its B and T cell immunogenicity, and might favor immune escape of tumor cells.

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“…Importantly, the in vitro GalNAc-transferase assay identified sites in the hypervariable V3 loop of different HIV and SIV isolates, and O-glycosylation could therefore mask this principal neutralizing epitope. In fact, the HIV-V3 sequence has been shown to contain a T-cell class I epitope, and the predicted glycosylation sites are positioned in the middle, thus presumably being able to mask the site (Ishioka et al, 1992;Mouritsen et al, 1994).…”

Section: Figmentioning

confidence: 99%

UDP-N-acetyl-α-D-galactosamine:polypeptide N-Acetylgalactosaminyltransferase

Sørensen

White

Wandall

et al. 1995

Journal of Biological Chemistry

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Using a defined acceptor substrate peptide as an affinity chromatography ligand we have developed a purification scheme for a unique human polypeptide, UDPGalNAc:polypeptide N-acetylgalactosaminyltransferase (GalNAc-transferase) (White, T., Bennett, E. P., Takio, K., Sørensen, T., Bonding, N., and Clausen, H. (1995) J. Biol. Chem. 270, 24156 -24165). Here we report detailed studies of the acceptor substrate specificity of GalNActransferase purified by this scheme as well as the GalNAc-transferase activity, which, upon repeated affinity chromatography, evaded purification by this affinity ligand. Using a panel of acceptor peptides, a qualitative difference in specificity between these separated transferase preparations was identified. Analysis of GalNActransferase activities in four rat organs and two human organs also revealed qualitative differences in specificity. The results support the existence of multiple GalNAc-transferase activities and suggest that these are differentially expressed in different organs. As the number of GalNAc-transferases existing is unknown, as is the specificity of the until now cloned and expressed GalNAc-transferases (T1 and T2), it is as yet impossible to relate the results obtained to specific enzyme proteins. The identification of acceptor peptides that can be used to discriminate GalNAc-transferase activities is an important step toward understanding the molecular basis of GalNAc O-linked glycosylation in cells and organs and in pathological conditions. Glycosylation of proteins in eukaryotes is fundamental for the integrity of the individual cell and the organism as a whole (Varki, 1993). A number of different types of protein glycosylations have been identified (for a recent review see Lis and Sharon, 1993). Biosynthesis of the initial glycosylation of the protein backbone has been established in most cases and the involved glycosyltransferases partly characterized. In several cases characterization of glycosylation sites has identified peptide motifs that suggest the nature of the acceptor substrate specificities of transferases initiating protein glycosylation.Thus N-linked asparagine glycosylation is restricted to the sequence -Asn-Xaa-Ser/Thr-(where Xaa may be any amino acid except proline). Proteoglycan-type glycosylation of serine is restricted to -Ser-Gly-Xaa-Gly- (Bourdon et al., 1987). The GlcNAc-type glycosylation of serine or threonine appears to be adjacent to an acidic amino acid and within two residues of a proline (Haltiwanger et al., 1992). The fucose-type glycosylation of serine/threonine seems to be restricted to the peptide sequence -Gly-Gly-Thr/Ser-Cys-, although the enzyme has yet to be characterized (Harris and Spellman, 1993).In contrast, a defined peptide motif for GalNAc O-glycosylation (mucin type) and the equivalent yeast Man-type glycosylation of serine/threonine has not emerged. A number of studies have attempted to identify a consensus sequence for mammalian GalNAc O-glycosylation by studying sequences around identified glycosylation sites (Goole...

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Major histocompatibility complex class II association and induction of T cell responses by carbohydrates and glycopeptides

Cited by 25 publications

References 23 publications

Differential immune responses to α-gal epitopes on xenografts and allografts: implications for accommodation in xenotransplantation

Differential immune responses to α-gal epitopes on xenografts and allografts: implications for accommodation in xenotransplantation

Tn Glycosylation of the MUC6 Protein Modulates Its Immunogenicity and Promotes the Induction of Th17-biased T Cell Responses

UDP-N-acetyl-α-D-galactosamine:polypeptide N-Acetylgalactosaminyltransferase

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