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Processing of Glycans on Glycoprotein and Glycopeptide Antigens in Antigen- Presenting Cells

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Processing of Glycans on Glycoprotein and Glycopeptide Antigens in Antigen- Presenting Cells Commentary Processing of glycans on glycoprotein and glycopeptide antigens in antigen- presenting cells Ole Werdelin*†, Morten Meldal‡, and Teis Jensen§ *Institute for Medical Microbiology and Immunology, University of Copenhagen, DK-2200 Copenhagen, Denmark; ‡Department of Chemistry, The Carlsberg Laboratory, DK-2500 Copenhagen, Denmark; and §Pharmexa A͞S, DK-2970 Hørsholm, Denmark ntil about 12 years ago, almost all an appropriate MHC class II molecule fine specificity of glycopeptide-specific T Uexperimental work with antigens ca- and obtain presentation to T helper cells. cells. Most common monosaccharides dif- pable of stimulating T cells had been The MHC class II molecule functions as a fer from one another by the orientation of performed with proteins and peptides, as receptor capable of binding 10–25 residue hydroxy groups. Progress in technology well as haptenated proteins and peptides. long peptide fragments of antigens with a has made it relatively easy to synthesize By far most of the work had been per- broad specificity and transporting them to glycopeptides with the same amino acid formed with mice that had been immu- the surface of the antigen-presenting cell sequence, but with closely related sugar nized and examined for responses in as- (APC) for presentation to T cells. In an groups differing only in the orientation of says for T cell proliferation. Pure immunogenic glycopeptide antigen, the the hydrophilic hydroxy groups attached carbohydrates were found to be incapable peptide provides the binding motif that to the same glycosylation site. Experi- of major histocompatibility complex enables the glycopeptide to bind to the ments with such sugar-variant glycopep- (MHC) binding and T cell stimulation (1, MHC molecule, and the glycan group tides have revealed the glycan group as an 2). However, within the last 10 years it has provides an important part of the struc- integrated part of the T cell epitope that become evident that both CD4ϩ and ture that constitutes the epitope, i.e., the ϩ may be recognized with high specificity. CD8 T cells can recognize glycopeptides structure that is recognized by the T cell One example is a large collection of gly- carrying mono- and disaccharides in a through its T cell receptor (TCR). Eu- copeptide-specific T cell hybridomas that MHC-restricted manner provided the gly- karyote protein glycosylation may be N- were unable of recognizing a glycopeptide can group is attached linked to asparagine or identical with the cognate glycopeptide COMMENTARY to the peptide at suit- O-linked to serine, except for the orientation of a single hy- able positions. In threonine, or hydroxy- T cell recognition of glycans droxy group (9). The glycan specificity is such glycopeptides, lysines. Studies of gly- reflected in the overall amino acid com- the primed T cells may be crucial for T cell copeptide recognition position of the central parts of the TCR’s recognize the glycan responses to autoantigens. by T cells have shown complementarity determining region structure with high fi- that a glycan group lo- (CDR3) of glycopeptide-specific T cell delity (see below). cated outside the pep- hybridomas and clones. Conserved amino The question of T cell tide binding core of the acid motifs and dominance of small polar recognition of glycopeptides may be im- MHC class II molecule will not be specif- amino acids, which are frequently found in portant in the immune defense against ically recognized, though it may change antibodies and other glycan-recognizing microorganisms, because many microbial the overall conformation of the MHC proteins, have been identified within antigens are in fact glycosylated. T cell bound peptide and in this way indirectly ␣␤TCR CDR3 regions of glycopeptide- recognition of glycans may also play an influence the structure of the MHC- specific T cells (12–14). In addition, amino bound T cell epitope (5, 6). In contrast, a important role in the immune defence acids that are flanking the glycan group glycan group positioned within the MHC against tumors, because one of the most and are oriented away from the binding binding core may influence the T cell consistent traits of a cancer cell is an cleft of the MHC molecule are recog- abnormal glycosylation of the proteins of recognition in several ways. If the glycan is linked to an amino acid functioning as an nized. The crystal structure of MHC class the malignant cell (3). In this issue of ͞ MHC anchor residue the glycopeptide I glycopeptide complexes also show that PNAS, Ba¨cklund et al. (4) provide evi- may be incapable of MHC binding and glycans can be accommodated by the TCR dence that T cell recognition of protein thus become nonimmunogenic (2, 7). (15, 16). However, not all peptide- glycans may be crucial also for T cell attached glycans can elicit a T cell re- However, if the glycan is linked to an ␣␤ responses to autoantigens in the course of amino acid pointing away from the bind- sponse (17). It appears that T cells are autoimmune diseases. Below we will de- ing site of the MHC molecule, the binding unable to recognize large and highly com- scribe and discuss the general rules for is maintained, and in antigens with the plex glycan structures. A possible molec- MHC class II restricted T cell recognition glycan attached to central residue within ular explanation for this may be that the of glycans, the fate of glycoprotein glycans the MHC core, the glycan becomes the during antigen processing, and the role of dominant structure in the epitope, which antigen glycosylation in tolerance to au- is recognized with very high fidelity by T See companion article on page 9960. toantigens and tumor antigens. cells specific for the particular glycopep- †To whom reprint requests should be sent at the present address: Institute for Medical Microbiology and Immunol- A sine qua non for a compound to be tide (7–11). ogy, The Panum Institute, Room 22.5.24, Blegdamsvej 3, able to stimulate an antigen-specific T Glycopeptides with simple sugars have DK-2200 N Copenhagen, Denmark. E-mail: o.werdelin@ helper cell response is that it can bind to been suitable for studies of the antigen immi.ku.dk. www.pnas.org͞cgi͞doi͞10.1073͞pnas.152345899 PNAS ͉ July 23, 2002 ͉ vol. 99 ͉ no. 15 ͉ 9611–9613 Downloaded by guest on September 29, 2021 clones only recognizing the unglycosy- lated form of the glycopeptide used for the immunization strongly indicates that deg- lycosylation of some of the antigen mole- cules had occurred during the priming phase of the immune response. The sig- nificance of deglycosylation may be quite different for various antigens, but should be considered. In the present study by Ba¨cklund et al. (4), some of the important glycopeptides obviously survive antigen processing with the glycan intact. Studies by Chicz et al. (20, 21) have shown that in natural glycoprotein pro- cessing some glycan groups remain at- tached to the antigen fragments bound onto MHC class II molecules. These work- ers eluted material bound onto the human HLA-DR and HLA-DQ molecules and identified some of them as glycopeptides containing N-linked GlcNAc residues. So far, however, N-linked carbohydrates have not been identified been identified on material eluted from MHC class I mole- cules. The majority of the MHC class I binding peptides are derived from cytoso- lic proteins that have been targeted by Fig. 1. Processing of glycoproteins in APCs. (A) The intact glycoprotein has been taken up by the APC and is transported through the endocytic pathway. (B–D) The peptide fragments after alternate glycan ubiquitinylation and degraded by the pro- processing. In all three, the peptide is in extended conformation. (B) The complex glycan group has teasome. The reason why these protein survived the processing and is left intact on the peptide fragment. (C) Only some of the glycan has survived fragments are devoid of sugars may be that bound to the glycosylated segment. (D) The glycan has been removed entirely. all sugars are removed by a cytosolic N- glycanase before the cytosolic protein in- teracts with the proteasome. By contrast, central CDR3 region of the TCR cannot with low pH optimum are added to the elution of peptides from MHC class I accommodate very large glycans, while endosome and the pH decreases progres- molecules have revealed that around other parts of the receptor at the same sively, leading to activation of the proteo- 0.1% of all class I bound peptides carry time interact with the ␣-helices of the lytic enzymes. The enzymes, which include small O-linked N-acetylglucosamine (O- presenting MHC molecule. Studies of the endoproteases and exoproteases of many ␤GlcNAc) residues (22). This finding is in immunogenicity of linear and branched different substrate specificities, attack and agreement with the fact that glycosylation sugars of varying length demonstrated fragment the antigen into peptides. Suit- of serine and threonine residues on that the ␣␤ TCR may recognize exten- able peptides bind to empty MHC class II nuclear and cytosolic proteins by O- sions of glycan groups consisting of up to molecules, which are accumulating within ␤GlcNAc are abundant in all multicellular three or four sugars, whereas even larger the acidic compartments and the peptides eukaryotes. In Ba¨cklund et al.’s paper in glycan structures lead to loss of MHC class are from that point on protected against this issue of PNAS (4) the authors dem- II restricted T cell recognition (16–18). further proteolysis (19). Finally, the onstrate that glycans not only remain at- Such large glycans may activate MHC MHC-peptide complexes are transported tached to the peptide backbone of the unrestricted ␥␦T cells, which recognize to the cell surface and presented to the T large glycoprotein antigen, collagen II the glycan antigen regardless of whether it cell system.
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