T cell recognition of Tn‐glycosylated peptide antigens

Abstract

The mouse hemoglobin-derived decapeptide Hb (67-76), VITAFNEGLK, which binds well to Ek and is non-immunogenic in CBA/J mice, was O-glycosylated with the tumor-associated carbohydrate Tn (alpha-D-N-acetylgalactosamine, or alpha-D-GalNAc). Each of the ten positions in the peptide was substituted with serine or threonine having the Tn antigen attached. The complete set of Tn-glycosylated peptides were then studied for binding to Ek and for immunogenicity in CBA/J mice. All of those glycopeptides which had the Tn attached to serine or threonine at a position in the peptide where, according to the crystal structure determinations, the amino acid side chain was oriented downwards into the binding site of the major histocompatibility complex (MHC) molecule, completely lost their capacity for binding to Ek. This was the case for the glycopeptides with Tn attached at position 68 and 76, which are the major anchor residues and for those with Tn attached at position 71 and 73, which function as secondary anchor residues. Those glycopeptides which had Tn attached to serine or threonine at positions where the side chain pointed away from the binding site maintained their capacity for binding to Ek, except for those with Tn attached at position 70 and 74. Furthermore, some of the MHC-binding glycopeptides were immunogenic. In particular, this was the case for the glycopeptide with Tn attached to the central position 72 in the decapeptide. From previous studies, this is known to be the dominant T cell receptor contact residue of Hb (67-76). The results suggest that T cells may be capable of recognizing epitopes which are partially defined by a small glycan group.

Identification, immunomodulatory activity, and immunogenicity of the major helper T-cell epitope on the K blood group antigen

“…This model has some parallel with immunogenicity of the platelet blood group HPA-1a, where the responsive Th repertoire is thought to be enhanced because the amino acid substitution in the antithetical HPA-1b sequence directly prevents binding to the restricting MHC molecule and thus induction of self-tolerance. 26,36 However, although addition of carbohydrate to key residues may reduce the ability of peptides to bind restricting MHC molecules, 37,38 in the case of k sequences, the glycosylation site N 191 is not predicted to be such an anchor. We, therefore, consider it more likely that the N-glycosylation interferes with T-cell recognition of the MHC-peptide complex.…”

The major T cell epitope on type II collagen is glycosylated in normal cartilage but modified by arthritis in both rats and humans

“…In the APC it has been shown that carbohydrates can play a role in protein assembly and folding, can provide protease protection and can also determine the orientation and location of the binding sites of the proteins [15][16][17]. In RA and CIA, cartilage proteins (including CII) typically undergo degradation by matrix metalloproteinases, leading to the generation of peptides that can bind to MHC II and then cause T cell activation.…”

A Mimic of Tumor Rejection Antigen-Associated Carbohydrates Mediates an Antitumor Cellular Response

“…Although these vaccines elicit antibody responses, it would also be advantageous if T cells could be directed to tumor-associated carbohydrate antigens (2)(3)(4)(5)(6). Posttranslationally modified cytosolic peptides carrying O-␤-linked N-acetylglucosamine (GlcNAc) can be presented by class I MHC molecules to the immune system that activate CTLs, as resolved by wheat germ agglutinin (WGA)-binding profiles reacting with GlcNAc containing glycopeptides in the MHC Class I binding site (7,8).…”