sign in sign up
<<
Home , Glycosylation

S22 Annals of the Rheumatic Diseases 1993; 52: S22-S29

Role of glycosylation in immune regulation Ann Rheum Dis: first published as 10.1136/ard.52.Suppl_1.S22 on 1 March 1993. Downloaded from

Elizabeth F Hounsell, Michael J Davies

Most cell surface and secreted are those of the outer branches of N-linked glycosylated - that is, they have one or more glycosylation (although there are differences). chains covalently attached to In both chains the diversity of oligosaccharide specific amino acids. These sequences is manifest in the large number of usually make up a significant amount of the ways the monosaccharides can be linked hydrodynamic mass of the molecules and also together (that is, through 1-4 hydroxyl groups, have effects on protein conformation, surface with and without branching, in (x or 3 expression, stability, circulating half life, configuration, etc). Each linkage has a activity, and antigenicity. In addition, oligo- particular set of allowed conformations in saccharide sequences are themselves solution which provide specific orientations of recognised as and as ligands for functional groups for molecular recognition. binding proteins (). The Such usually extend over a tri- to exemplifies the diversity of heptasaccharide sequence, but topographical oligosaccharide structure and function, which epitopes caused by folding back of long this review will aim to communicate. In carbohydrate chains onto themselves or onto particular, the relevance of oligosaccharide protein are possible. In addition, the oligo- heterogeneity, antigenicity, and immune saccharide cores of 0-linked chains are in close regulatory activity in autoimmunity and association with the protein backbone, which microbial pathogenesis will be considered. strongly influences protein conformation and Firstly, a general description of the structure oligosaccharide-protein antigenicity.' Often and three dimensional arrangement of protein multiple 0-glycosylation sites are clustered in glycosylation will be given. Then, we describe one region of the protein to accentuate these the structure of the major effector conformational effects (for example, CD8 molecules involved in immune regulation and discussed below). concentrate on the role of T cell -y 8 cells in N-linked chains are in general less tuberculosis and (RA). stereochemically restricted around the protein- oligosaccharide linkage than their 0-linked General description ofprotein counterparts, and, in addition, have

glycosylation (also see Glossary) considerable flexibility at branch points within http://ard.bmj.com/ Protein glycosylation is of two major types the chain. The oligosaccharide moieties, called N- or 0-linked depending on the linkage therefore, sample a large amount of of the oligosaccharide chain through conformational space, but in some cases they (NH2) or / (OH), may be restrained by interaction with the respectively. N-linked chains typically have a protein backbone or adjacent oligosaccharides pentasaccharide core of (Man) and attached to the same protein. The paradigm for

N-acetylglucosamine (GlcNAc) residues with protein-to-N-glycosylation interaction is the on October 1, 2021 by guest. Protected copyright. additional mannose residues (high mannose Fc region of IgG where electron density for chains) or backbone -N-acetyl- oligosaccharides has been shown by x ray glucosamine sequences with and without chain crystallography which can be interpreted as terminating residues (complex constraints by the protein to impose a single chains). Hybrid chains are defined as those conformational state.' In other having some high mannose branches and some that have been characterised by x ray complex-type sequences. The core and crystallography the oligosaccharide conform- backbone residues of complex chains are ation could not be discerned at high resolution variously decorated with blood group and - for example, studies of the major histocom- related antigenic sequences involving substitu- patibility complex (MHC) glycoprotein tion with , (Fuc), N-acetylgalactosamine molecule HLA-A2.6 For still further (GalNAc), and galactose (Gal).' 2 The glycoproteins, crystals of sufficiently high presence of the different chains can be quality for x ray crystallography are not formed distinguished not only by chemical unless some of the glycosylation is modified. composition but also by their susceptibility to This can be for the reasons already mentioned digestion - all are released by peptide- - that is, large hydrodynamic volume (in N-glycosidase F, whereas endoglycosidase H particular when multiple glycosylation is Clinical Research only releases mannose chains. present); effects on protein conformation; or, Centre, Watford Road, high Harrow, Middlesex 0-linked glycosylation discussed in this inherent oligosaccharide flexibility. An HAl 3UJ, United article is characterised by core regions based on additional factor, discussed next, is the Kingdom N-acetylgalactosamine linked to protein, with microheterogeneity of oligosaccharide struc- E F Hounsell M J Davies galactose, N-acetylglucosamine, or N-acetyl- ture at each glycosylation site within a protein. attached. Extension of the Because of the difficulties of their visualisation Correspondence to: galactosamine 1- Dr Hounsell. chains is by substitution patterns similar to by x ray studies the characterisation of protein Role ofprotein glycosylation in immune regulation S23

glycosylation has largely relied on enzymatic, further glycosylation patterns found in, for

gel, and chromatographic methods of analysis example, parasite and mammalian glycophos- Ann Rheum Dis: first published as 10.1136/ard.52.Suppl_1.S22 on 1 March 1993. Downloaded from with, when possible, high resolution physi- phatidylinositol anchors'4 and bacterial cochemical techniques (in particular, mass , including peptido- spectrometry and nuclear magnetic resonance , capsular , and

spectroscopy).24 7 0--type specific lipopolysaccha- rides.'5 16 These molecules are highly antigenic, but in the case of lipopoly- Microheterogeneity of oligosaccharide saccharides and peptidoglycan are more likely sequences of glycoproteins to exert their arthritogenic affect by mechan- All glycoproteins exhibit heterogeneity such isms involving direct mitogenicity.'5 The that they exist as a population having a mammalian are an additional spectrum of oligosaccharide sequences (glyco- type of glycosylation which needs to be forms). Variation occurs in the number and discussed in this context. One of the initial length of branches (or antennae) leading from responses in the rheumatoid joint is breakdown the cores, together with alterations in sequence of the proteoglycans which, together with and peripheral substitutions. Of relevance to , make up cartilage. Hyperimmun- the present article is the documentation of the isation with host proteoglycans will lead to glycoforms of IgG where a large number of experimental arthritis. ' Proteoglycans are different biantennary N-linked chains were classically very high molecular weight found, including some having short chains molecules of different uronic acid-hexosamine exposing GlcNAcp residues to which Gal repeating disaccharide sequences having residues and additional substitutions are multiple variable sulphation.'8 Relatively short normally linked.8 The presence ofthese chains, regions of sequences, however, termed Galo is suggested to be a marker of RA can also be found on membrane-type that may be functional by reducing the glycoproteins - for example, the invariant intramolecular oligosaccharide-to-protein chain of class II MHC'9 and lymphocyte interaction discussed above or by effecting antigen CD44.2" Therefore besides direct binding to GlcNAc, specific endogenous damage to the joint, the induced in lectins, or both. This binding would have to be arthritis which degrade proteoglycans may also specific to the GlcNAcP1-6/4/2Man sequence directly affect T cell function. Proteoglycans as GlcNAc, 1-3Gal and GlcNAccx1-4Gal are are also common constituents of secretory found quite commonly as chain terminating granules of a variety of haemopoietic cells.2' In groups in mucms.- mast cells evidence is accumulating for their The studies quoted in reference 8 were function during degranulation in controlling carried out on IgG pooled from human serum. the release of mast cell proteases,22 which are From other studies it is known that the mediators of allergic inflammatory glycoproteins from single donors can also show reactions. In addition, proteoglycans at considerable heterogeneity - for example, endothelial cell membranes are necessary for http://ard.bmj.com/ more than 250 different glycoforms from the an intact microvasculature, the breakdown of Tamm-Horsfall proteins of the urine of one which is an essential component of the donor.9 There is also considerable variation in rheumatoid process.23 cell-cell glycosylation - for example, in Other glycoproteins are being increasingly glycoproteins from single cell lines.'0 The implicated in the inflammatory process - in structural changes in IgG are also mirrored in particular, the recruiting ofneutrophils to areas cell studies from patients with RA" or from the of endothelial cell damage. Studies have shown on October 1, 2021 by guest. Protected copyright. lpr autoimmune mouse model.'2 These studies that particular oligosaccharide structures on a provide support for the contention that subset of neutrophil glycoproteins are particular clones of B cells can be stimulated recognised by the selectin ELAM- 1 induced on to express immunoglobulins of a restricted activated endothelial cells.24 The major phenotype.'3 Since the original observations of oligosaccharide structure involved, called sialyl Galo in rheumatoid patients8 several other Lewis X, belongs to a family of previously immune disorders, granulomatous-type characterised oligosaccharide differentiation diseases such as tuberculosis, and age matched antigens25 which have now found a role in controls have shown the prevalence of this type cellular interactions. These interactions are of IgG glycosylation."1 Although, in general, influenced by cytokines such as tumour there is a large variability in the glycosylation necrosis factor.26 Other cytokines, the of glycoproteins in normal and diseased states, interleukins IL-1 and IL-2, have been shown the Galo phenotype remains relatively to have properties and respectively bind restricted to IgG. The relevance of this to Tamm-Horsfall glycoprotein27 (also called observation within the context of the uromodulin when found in the urine of complexity of autoimmunity remains obscure. pregnant females with more glycosylation than This review explores other areas where protein the Tamm-Horsfall glycoprotein discussed glycosylation may play a part in immune above) and high mannose oligosaccharides.28 regulation. This may explain the well known immuno- suppressive effect of the oligosaccharides of Tamm-Horsfall glycoprotein/uromodulin and Direct role ofprotein glycosylation also of the high mannose chains of yeast. A In addition to the heterogeneity in the types of second mechanism for the immunosuppressive glycoprotein chains discussed above, there are effects of polysaccharides of microbial origin is S24 Hounsell, Davies

their uptake by macrophages and disruption of which they are attached and this is particularly the normal paths of antigen presentation.29 true of the multiple 0-glycosylation found, for Ann Rheum Dis: first published as 10.1136/ard.52.Suppl_1.S22 on 1 March 1993. Downloaded from Mention should also be made here of (a) the example, on the receptor for IL-234 and on lectin properties of IgD30; (b) the strong CD8. The first evidence for the importance of homologies between a rat IgE binding protein 0-glycosylation in lymphocyte antigens was and galactose binding proteins such as CBP35 reported for CD45.35 For CD8 it has been and Mac-2 macrophage antigen31; and (c) the shown36 that 0-glycosylation must be removed glycosylation inhibiting factor, which alters the before crystallisation can take place for x ray glycosylation of IgE binding proteins causing crystallography studies. Interestingly, the selective suppression of IgE synthesis.32 related molecule CD4, which has a role equivalent to that of CD8 in their respective binding to class I and class II MHC Effect ofglycosylation on immune protein molecules,37 has a very different glycosylation function pattern with no reported 0-glycosylation but In addition to the specific functions of having four possible N-linked sites, the oligosaccharides in immune regulation, glyco- occupancy of which is a prerequisite for correct sylation has several regulatory effects on folding and membrane expression.38 MHC protein function and recognition. The molecules are themselves glycosylated and this oligosaccharide chains of glycoproteins tend to can influence antigen presentation.39 In fig 1 cover a large surface area inhibiting immune we have chosen to illustrate the relative sizes recognition and processing of the underlying and orientation of a single oligosaccharide protein. Many of the effector molecules in chain as present on the human class I MHC immune regulation, including the immunoglo- molecule HLA-A2. It depicts the minimum bulins mentioned above, are glycosylated. The sized N-linked complex chain which in the cytokine receptors so far characterised are native molecule could have additional glycoproteins, as are some of the cytokines branches and peripheral substitution. As themselves.33 Oligosaccharides are known to discussed, most glycoproteins have more than influence the conformation of the protein to one glycosylation site. Figure 2 presents a

Antigen binding pocket -4 http://ard.bmj.com/

Oligosaccharide on October 1, 2021 by guest. Protected copyright.

Figure 1 A computergraphics molecular model ofMHC class I HLA-A2 ar ta3 domains (270 amino acids) takenfrom Brookhaven files ofcrystallographic studies carried out by Bjorkman et al.6 The protein backbone is accentuated with a ribbon. The a, and a2 region a helices surround the antigen bindingpocket. A disialyated biantennary nonasaccharide is attached at the consensus N-linked glycosylation site, Asn 86 (top right), at the end ofthe a, a helix. This represents one ofmany possible solution conformers ofthe oligosaccharide chain which will explore space within a dome ofthe dimensions shown. Modelling was carried out using Biosym software on a silicon graphics IRIS workstation. Role ofprotein glycosylation in immune regulation S25

CD44 CD4 CD8 TCR

Of af Ann Rheum Dis: first published as 10.1136/ard.52.Suppl_1.S22 on 1 March 1993. Downloaded from

415 28 1 75 P 425 4 80 4125 457 145 > 117- 4119 1180 4120 4100 119@ 124 4161 4110 179 > 4 4127 120 126* 4128 130- 190 N 4141 180 U 273 l 133* 190 U 137 * 300Q 231 U -SH 4254 -SH 257 U 226 P Lull-

Figure 2 The glycosylation patterns ofthe human T cell glycoproteins CD44, CD4, CD8 (ao8 heterodimer), and the T cell receptor (HPB-MLT a chain, HPB-ALL ,B chain). Consensus N-glycosylation sites are denoted by *, characterised 0-glycosylation sites by *, aindpotential proteoglycan attachment sites by U. SH representsfree cysteines capable of forming interchain disulphide bridges and -S-S represents interchain disulphide bridges.

synopsis of the oligosaccharide chains of A more complicated pattern of cell specific CD44, CD4, CD8 aot, and the T cell receptor glycosylation of T cell yb receptors has (TCR) a,B chains showing their various emerged (fig 3), which we discuss here in full glycosylation patterns taken from references to illustrate the type of diversity encountered, 20, 36, 38, and 40-43. together with the evidence implicating this T http://ard.bmj.com/ Type 1 T1 ype 2abc Type 2bc

106 on October 1, 2021 by guest. Protected copyright.

* 132 4132 4132

202 > 179 t 140 4195 4195 4195

r/ 249 , 193 N 257> I 265 -SH 209l - SH 26310 111 271 1 I 215k 272k 280 N 224k SH -SH -SH Liz -SH -SH- -SH- SH -SH -SH __ -SH 8 SH -SH

'Y Y

Figure 3 The diversity of yb T cell receptor structures; glycosylation sites are classified as infig 2. 111 represents the Cyl C2 exon; M represents the C-y2 C2 exon copy a; 3 represents the Cy2 C2 exon copy b; * represents the C-y2 C2 exon copy c. S26 Hounsell, Davies

cell subset in the aetiology of RA and although if the type 2 receptors are expressed, tuberculosis. types 1 and 2 are usually found in equal Ann Rheum Dis: first published as 10.1136/ard.52.Suppl_1.S22 on 1 March 1993. Downloaded from proportions.47 This diversity of T cell receptors T cell -y receptor structure is unique to y8 T cells and as yet no distinct The TCR 8 chain is a polypeptide of 40 functional roles have been attributed to either kilodalton size with two N-linked glycosylation TCR type, though a report has suggested sites (one high mannose oligosaccharide and different cytoskeletal organisation and one complex oligosaccharide, as determined by morphology between the Cy 1 and Cy2 endoglycosidase H and peptide N-glycanase F forms.49 digests).44 In addition, there are two intra- Like o43 TCRs, ry8 TCRs are associated with molecular disulphide bridges and potential for the CD3 glycoprotein to facilitate cell one intermolecular disulphide bridge.44 4 In T signalling and activation. The CD3 'y8E cell lines y chains exhibit much more structural peptide cores are the same for both T cell diversity, being expressed as one of three subsets (c43 and y8).f0 However, glycosylation forms. All three forms have two intramolecular of the CD38 subunit is different. In ot3 T cells disulphide bridges and at least two potential the CD38 subunit carries one high mannose N-glycosylation sites. The type 1 receptor was and one complex oligosaccharide,5' whereas in first isolated from a peripheral blood y6 T cells both oligosaccharides are fully lymphocyte cell line.45 This form expresses two processed to the complex form.50 y6 CD3 glycoforms of the y chains, a 40 and a 36 seems to increase intracellular calcium on kilodalton form, both forms containing four triggering and is a substrate for protein kinase N-linked glycosylation sites.46 Treatment with C activation.52 53 Thus if the different endoglycosidase H reduced both glycoforms to glycosylation is important it may function in a core peptide of 31 kilodaltons.45 This the regulation of T cell signalling via the -y indicates differential glycosylation of the two TCR/CD3 pathway. peptides, notably in the distribution of high mannose and hybrid oligosaccharides. The Role ofTCR y8 cells in antigen and type 1 receptor uses the Cy1 gene. Within this, superantigen recognition one copy of the C2 exon is expressed, Heat shock proteins are the major antigens containing two consensus N-glycosylation sites described to be recognised by -y8 T cells. In and a cysteine residue. This cysteine is able to both a live and heat killed Mycobacterium crosslink with the cysteine of the 8 chain tuberculosis infection model, -yb T cells forming a disulphide bridge.44 It is this feature produced interferon -y, granulocyte-monocyte which is the main distinguishing characteristic colony stimulating factor, IL-3, and tumour of the type 1 receptor. necrosis factor Ol.5 The nature of the dominant In addition to the type 1 form, two non- antigen or antigens recognised remains to be intermolecular disulphide linked forms of the characterised fully as up to 400 different receptor have been described.44 45 The 8 chains components may be involved,55 but the

are similar to those expressed by the type 1 mycobacterial 65 kilodalton heat shock protein http://ard.bmj.com/ receptor, but the -y chains show significant (hsp65) is a major contender56 57 and, in diversity in their constant regions.44 Both forms particular, a peptide corresponding to residues use the C-y2 gene for their constant region. The 181-195.58 59 Heat shock proteins are a highly 2abc form expresses three copies of the C2 conserved set of proteins with both bacterial exon (copies a, b, and c). The resulting and mammalian homologues. The 60 polypeptide has a size of 55-60 kilodaltons, kilodalton family (including M tuberculosis

which reduces to 40 kilodaltons on endogly- hsp65) is thought to influence the folding and on October 1, 2021 by guest. Protected copyright. cosidase H treatment, again showing differ- trafficking of mitochondrial proteins.606' ential glycosylation and the probable use of all The 65 kilodalton heat shock protein has five consensus N-glycosylation sites. been described as a possible antigen in several The second non-disulphide linked form of autoimmune disorders. It has been suggested the receptor (type 2bc) expresses two copies of to be a putative yb T cell ligand on Daudi the C2 exon (copies b and C).44 This results in cells67 and a ligand on B cells in lupus a glycosylated peptide of 40 kilodaltons, which nephritis.63 Rheumatoid arthritic synovial fluid reduces to 35 kilodaltons, on endoglycosidase -y8 T cells reactive to M tuberculosis were first H treatment. The sequence gives isolated in 1989,64 with one clone reacting to a theoretical non-glycosylated size of 34-8 the hsp65 of M bovis-BCG. An earlier rat kilodaltons, which together with tunicamycin model of adjuvant arthritis had shown the data (an inhibitor of N-linked glycosylation) antigenicity of hsp65 peptide 180-188,65 shows the glycosylation to be essentially all though this is only present in the N-linked.44 The 5 kilodalton loss in molecular bacterial protein and not its mammalian weight indicates that unlike the type 2abc homologue. More recently, both -yb and ot3 T receptor only two of the six possible cell clones have been isolated, which are glycosylation sites are used. The differences in stimulated by both mycobacterial and human the number of glycans added can be explained hsp65, supporting the possibility of hsp65 by the fact that the protein encoded by the C2a involvement in autoimmune disorders.66 67 exon copy has an altered secondary or tertiary Data for hsp65 as a major antigen of RA are structure making more of the 2abc y chain not entirely conclusive.68 A recent review has consensus N-glycosylation sites accessible.47 shown that recombinant hsp65 from Expression of the type 1 receptor is also contained small quantities predominant in peripheral blood lymphocytes, of E coli derived antigens.69 Thus stimulation Role ofprotein glycosylation in immune regulation S27

of rheumatoid T cells by the recombinant rheumatoid synovial fluid noted the

hsp65 may in fact be by contaminating E coli requirement of antigen presenting cells for Ann Rheum Dis: first published as 10.1136/ard.52.Suppl_1.S22 on 1 March 1993. Downloaded from antigens. Coupled with this, a second group stimulation by mycobacterial antigens, but this has found that highly purified M bovis-BCG was suggested not to be class I or class II hsp65 is poorly stimulatory, leading the restricted.64 Later a class II restricted V-y982 T authors to conclude that hsp65 is not a major cell response was characterised against a antigen for rheumatoid synovial fluid T cells.70 tetanus toxin peptide.78 However, only a small The role of hsp65 in RA is thus not clear cut percentage of yyb T cells are CD4+; the and it may be that hsp65 continues the majority express either CD8&x chains only, or degenerative disease process after stimulation are CD4-CD8-, and it has been suggested that by a different antigen.7' It is of interest here CD4+ y8 T cells are more likely to be a fetal that heat shock protein may mimic the MHC T cell subset which has persisted postnatally.9" in a similar manner to that proposed for HIV In general, y8 and (o3 T cells produce a similar gp 1 20.72 73 range of cytokines,92 but the proposed minor No alternative mycobacterial antigens of subset of CD4+ -y8 T cells shows production possible relevance for human RA have yet been of IL-2 and granulocyte-monocyte colony characterised. Mycoplasmal mitogens have stimlating factor and low levels of cytotoxic been proposed in murine models.74 7 activity, whereas the CD4- y8 T cells exhibit Superantigen stimulation has been used to lower levels of cytokine production and a explain the increased usage of VP 14 ot3 T cells higher cytotoxic activity.93 Based on this yi T in RA.76 In addition, the superantigen cells can be subdivided into a CD4+ 'helper' staphylococcal enterotoxin D has been shown subset and a CD4- 'cytotoxic' subset. to stimulate CD4 V16 (o3 T cells to produce rheumatoid factors.77 There is also evidence that superantigens may stimulate -y6 T cells in Conclusion RA: Vy982 T cell clones from rheumatoid Study of the possible role of superantigens in arthritic synovial fluid have been shown to autoimmune disorders has recently become the recognise a short tetanus toxin peptide in the vogue. Care should be exerted in interpretation context of MHC class II78; this Vy982 subset of the data, however, owing to the complexity may be stimulated by tne acetone precipitable of the interactions of the effector molecules fraction of M tuberculosis.78 79 There is also involved in immune regulation. An important evidence for clonal expansion of V-y9 T cells in aspect of these interactions is the role of the synovial fluid of patients with RA.80 glycosylation in regulating glycoprotein Similarly, in M tuberculosis infection there is activity, antigenicity, and recognition. increasing evidence that hsp65 is not a major Protein glycosylation may be involved in -y T cell antigen, and indeed there is some several stages in the aetiology of RA: (a) evidence that it may be a poor M tuberculosis initiating antigen; (b) control of T cell inter- antigen in general.82 The major subset of y5 T actions; (c) control of function; (d) cells which expands in response to M microvasculature breakdown; (e) breakdown of tuberculosis is Vy982, which predominantly synovial gel/water structure; and () specific http://ard.bmj.com/ express the C-y1 form of the TCR discussed signals to inflammatory cells. above.83 84 The same V y9 subset has been Of crucial importance is the role that shown to be stimulated by the superantigen, proteoglycan sequences have in maintaining staphylococcal enterotoxin A,85 which requires the endothelial cell surface barrier, the the presence of the MHC class II. This is physicochemical properties of the synovium, to the activation of ot3 cells and cartilage structure. The release of enzymes directly analogous on October 1, 2021 by guest. Protected copyright. by superantigens.86 A second VWy9-seeking which breakdown these proteoglycans could superantigen has been isolated from M also directly affect lymphocyte immune tuberculosis, 6 87 again requiring MHC class II. function by altering cell surface molecules and The antigen seems to be a low molecular intracellular trafficking. weight, protease resistant ligand which loses its antigenicity on incubation with the plant lectins UEA1, SBA, and DBA. Thus it has Glossary been postulated that the active components are CD: Clustered Determinant lymphocyte antigens. glycosylated determinants having chain Consensus N-glycosylation site: The (N) ofthe terminating ot-linked fucose and GalNAca(1- Asn amino acid in the sequence Asn-X-Ser/Thr has 3)GalNAc for which these lectins are specific.87 the potential to be glycosylated, where X is any amino This is important not only from the point of acid except proline. view of M tuberculosis infection but is the first time a possible non-protein superantigen has N-linked protein chains: high mannose been described. complex The mechanism by which antigens are hybrid presented to -yi T cells remains largely 0-linked glycoprotein chains: The hydroxyl group of unresolved. Conflicting reports exist on the any Ser or Thr amino acid usually in high Ser/Thr/ requirement for P2 microglobulin and hence Pro- containing regions is glycosylated. class I restriction of -y8 T cells,88 89 though the Peptidoglycan: Repeating bacterial cell wall polymer of requirement may depend on the T cell type amino acids, muramic acid, and N-acetylglucos- studied. Restriction by non-classical class I amine. molecules including Qa-1, has been shown.90 The initial discovery of -yb T cells in Polysaccharides: In addition to plant (e.g. cellulose) and S28 Hounsell, Davies

mammalian (e.g. glycogen) polymers, have 24 Lowe J B, Stoolman L M, Nair R P, Larsen R D, Berhend T L, Marks R M. ELAM-1-dependent cell adhesion to

chain molecules of often Ann Rheum Dis: first published as 10.1136/ard.52.Suppl_1.S22 on 1 March 1993. Downloaded from diverse long complex vascular endothelium determined by a transfected human repeats defined as: (a) capsular antigens (b) fucosyltransferase cDNA. Cell 1990; 63: 475-84. 0-antigen lipopolysaccharide (LPS). 25 Feizi T. Cell-cell adhesion and membrane glycosylation. Current Opinlionis in Structuiral Biology 1991; 1: 766-70. 26 Gamble J R, Smith W B, Vadas M A. TNF modulation of Proteoglycan: Components of mammalian extracellular endothelial and neutrophil adhesion. In: Beutler B, ed. matrix, membrane cell surface molecules, secretory Ttionour necrosisfactors: the miiolecules and their cpnergilig role granules, and cartilage. i?nmedicine New York: Raven Press, 1992: 65-86. 27 Muchmore A V, Decker J M. Evidence that recombinant ILl A exhibits lectin-like specificity and binds to Selectin: Mammalian carbohydrate binding protein also homogeneous uromodulin via N-linked oligosaccharides. called leccams (lectin cell adhesion molecules). Immunol 1987; 138: 2541-6. 28 Sherblom A P, Sathyamoorthy N, Decker J M, Muchmore A V. IL-2, a lectin with specificity for high mannose glycoproteins. JlmnImunol 1989; 143: 939-44. 29 Harding C V, Roof R W, Allen P M, Unanue E R. Effects of pH and polysaccharides on peptide binding to class II major histocompatibility complex molecules. Proc Natl 1 Hounsell E F, Feizi T. Gastrointestinal . Structures Acad Sci USA 1991; 88: 2740-4. and antigenicities of their carbohydrate chains in health 30 Amin A R, Lakshmi Tamma S M, Oppenheim J D, et al. and disease. Med Biol 1982; 60: 227-36. Specificity of the murine IGD receptor on T cells is for 2 Hounsell E F, Davies M J, Renouf D V. Studies of N-linked glycans on IgD molecules. Proc Natl Acad Sci oligosaccharide and glycoprotein conformation. Biochemi USA 1991; 88: 9238-42. Soc Trans 1992; 20: 259-63. 31 Cherayil B J, Weiner S J, Pillai S. The mac-2 antigen is a 3 Hounsell E F, Lawson A M, Stoll M S, et al. galactose-specific lectin that binds IgE. _7 Exp Med 1989; Characterisation by mass spectrometry and 500-MHz 170: 1959-72. proton nuclear magnetic resonance spectroscopy of 32 Katamura K, Iwata M, Mori A, Ishizaka K. Biochemical penta- and hexasaccharide chains of human foetal identification of glycosylation inhibiting factor. Proc Natl gastrointestinal mucins (meconium glycoproteins). Eur.7 AcadSci USA 1990; 87: 1903-7. Biochem 1989; 186: 597-610. 33 Arai K-I, Lee F, Miyajima A, Miyatake S, Arai N, Yokota 4 Chai W, Hounsell E F, Cashmore G C, et al. Neutral T. Cytokines: coordinators of immune and inflammatorv oligosaccharides of bovine submaxillary . A responses. Annu Rev Biochemn 1990; 59: 783-836. and 'H-NMR 34 Nikaido Shimizu Ishida N, et al. combined mass spectrometry study. Eur_ T, A, IL2 receptor Biochem 1992; 203: 257-68. structure. Nature 1989; 311: 631-5. 5 Rudd P M, Leatherbarrow R J, Rademacher T W, Dwek 35 Childs R A, Dalchau R, Scudder P, Hounsell E F, Fabre R A. Diversification of the IgG molecule by J W, Feizi T. Evidence for the occurrence of oligosaccharides. Mol Immiunol 1991; 28: 1369-78. 0-glycosidically linked oligosaccharides of poly- 6 Bjorkman P J, Saper M A, Samraoui B, Bennett W S, N-acetyllactosamine type on the human leucocyte Strominger J L, Wiley D C. Structure of the human class common antigen. Biochemn Biophys Res ComnipiunI 1983; I histocompatibility antigen, HLA-A2. Nature 1987; 329: 110: 424-31. 506-12. 36 Leahy D J, Axel R, Hendrickson W A. Crystal structure of 7 Hounsell E F. Structural and conformational a soluble form of the human T cell coreceptor CD8 at 2.6 characterization of carbohydrate differentiation antigens. A resolution. Cell 1992; 68: 1145-62. Chem Soc Rev 1987; 16: 161-85. 37 Parham P. The box and the rod. News and views CD8 and 8 Sutton D L, Fernandes A, Leung D, et al. Primary sequence CD4. Nature 1992; 357: 538. of the N-linked oligosaccharides associated with IgG. 38 Tifft C J, Proia R L, Camerini-Otero R D. The folding and Nature 1985; 316: 452-7. cell surface expression of CD4 requires glycosylation. _7 9 Hard K, van Zadelhoff G, Moonen P, Kamerling J P, Biol Chem 1992; 267: 3268-73. P. N-linked Vliegenthart J F G. The Asn-linked carbohydrate chains 39 Neefjes J J, De Bruijn M L H, Boog C J et al. of human Tamm-Horsfall glycoprotein. Novel sulfated modification on antigen-presenting cells restores and novel GalNAc-containing N-linked carbohydrate an allospecific cytotoxic T cell response. N Engl Med chains. Eur_7Biochem. 1992; 209: 895-915. 1990; 10: 533-88. 10 Hard K, Damm J B L, Spruiit M P N, et al. The 40 Pascale M C, Malagolin N, Serafini-Cessi F, Migliaccio G, carbohydrate chains of the ,B subunit of human chorionic Leone A, Bonatti S. Biosynthesis and oligosaccharide produced by the choriocarcinomas cell line structure of human CD8 glvcoprotein expressed in a rat BeWo. Novel 0-linked and novel bisecting-GlcNAc- epithelial cell line. Y Biol Chemi 1992; 267: 9940-7. containing N-linked . Eur 7 Biochem 1992; 41 Norment A M, Littman D R. A second subunit of CD8 is http://ard.bmj.com/ 205: 785-98. expressed in human T cells. EMBO37 1988; 7: 3433-9. 11 Bodman K B, Sumar N, MacKenzie L E, et al. 42 Saito H, Kranz D M, Takagaki Y, Hayday A C, Eisen H Lymphocytes from patients with rheumatoid arthritis N, Tonegawa S. Complete primary structure of a produce agalactosylated IgG in vitro. Clin Exp Irnniunol heterodimeric T-cell receptor deduced from cDNA 1992; 88: 420-3. sequences. Nature 1984; 309: 757-62. 12 Mizuochi T, Hamako J, Nose M, Titani K. Structural 43 Yoshikai Y, Anatoniou D, Clark S P, et al. Sequence and changes in the oligosaccharide chains of IgG in expression of transcripts of the human T-cell receptor autoimmune MRIJMp-lpr/lpr mice. _7 Immunol 1990; 3-chain genes. Nature 1984; 312: 521-4. 145: 1794-8. 44 Hochstenbach F, Parker C, McLean J, et al. R Malcolm A D B. Characterization of a third form of the human T cell 13 Haynes G A, Maini N, Immunoglobulin on October 1, 2021 by guest. Protected copyright. V genes expression and mRNA sequencing in rheumatoid receptory/8. YExp Med 1988; 168: 761-76. arthritis. Ann Rheum Dis 1990; 49: 460-8. 45 Brenner M B, McLean J, Scheft H, et al. Two forms of the 14 Ferguson M A J. Lipid anchors on membrane proteins. T-cell receptor y protein found on peripheral blood Current Opinions in Structural Biology 1991; 1: 522-9. cytotoxic T lymphocytes. Nature 1987; 325: 689-94. 15 Stimpson S A, Esser R E, Carter P B, Balfour Sartor R, 46 Krangel M S, Band H, Hata S, McLean J, Brenner M B. Cromartie W J, Schwab J H. Lipopolysaccharide induces Structurally divergent human T cell receptor y proteins recurrence of arthritis in rat joints previously injured by encoded by distinct C-y genes. Science 1987; 237: 64-7. peptidoglycan-. _7 Exp Med 1987; 165: 47 Band H, Hochstenbach F, Parker C M, McLean J, Krangel 1688-702. M S, Brenner M B. Expression of human T cell receptor- 16 Jennings H. Capsular polysaccharides as human vaccines. ½y structural forms. YIJmmnunol 1989; 142: 3627-33. Adv Carbohydr Chenm Biochem 1983; 41: 155-208. 48 Littman D R, Newton M, Crommie D, et al. 17 Leroux J-Y, Poole A R, Webber C, et al. Characterization Characterization of an expressed CD3 associated Ti of proteoglycan-reactive T cell lines and hybridomas from -y-chain reveals a C-y domain polymorphism. Natuire 1987; mice with proteoglycan-induced arthritis. _7 Immunol 326: 85-8. 1992; 148: 2090-6. 49 Grossi C E, Ciccone E, Migone N, ct al. Human T cells Cyl 18 Poole A R. Proteoglycans in health and disease: structures expressing the -y/8 T-cell receptor (TcR- 1): -and and functions. 1986; 236: 1-14. C-y2-encoded forms of the receptor correlate with Biochem37 and 19 Sant A Cullen S E, Giacoletto K S, Schwartz B D. distinctive morphology, cytoskeletal organization, J, 86: Invariant chain is the core protein of the Ia-associated growth characteristics. Proc Natl Acad Sci USA 1989; chondroitin sulfate proteoglycan. .7 Exp Med 1985; 162: 1619-23. 1916-34. 50 Krangel M S, Bierer B E, Devlin P, et al. T3 glycoprotein distinct on human 20 Stamenkovic I, Amiot M, Pesando M, Seed B. A is functional although structurally J USA lymphocyte molecule implicated in lymph node homing T-cell receptor y T lymphocytes. Proc Natl Acad Sci is a member of the cartilage link protein family. Cell 1989; 1987; 84: 3817-21. Elder Terhorst C. The T3 complex 56: 1057-62. 51 Borst J, Alexander S, J, on human T involves four structurally 21 Steward W P, Christmas S E, Lyon M, Gallagher J T. lymphocytes Chem 258: 5135-4 1. T distinct _7 synthesis of proteoglycans by human lymphocytes. glycoproteins. Biol 1983; 52 H Terhorst C, Cantley L C, Roseoff P H. Biochim Biophys Acta 1990; 1052: 416-25. Oettgen C, Stimulation of the cell receptor complex induces a 22 Le Trong H, Newland G F J, Miller H R P, Charbonneau T3-T calcium influx. Cell 1985; H, Neurath H, Woodbury R G. Amino acid sequence of membrane-potential-sensitive 40: a mouse mucosal mast cell protease. Biochemistry 583-90. Samelson L E. A 28: 391-5. 53 Wange R L, Tony Kong A-N, - 70-kDa protein binds a photoaffinity 23 Lopes-Virella M F, Virella G. Immunological phosphorylated of ATP and associates with both the C chain and microbiological factors in the pathogenesis analogue CD3 of the activated T cell antigen receptor. atherosclerosis. Clin Immunol Immunopathol 1985; components Biol Cheii 267: 377-86. 7 1992; 11685-8. Role ofprotein glycosylation in immune regulation S29

54 Bames P F, Grisso C L, Abrams J S, Band H, Rea T H, carboxyl terminus of HIV-1 gpl20 showing structural Modlin R L. yb T lymphocytes in human tuberculosis. features consistent with the presence of a T-cell J3InfectDis 1992; 165: 506-12. alloepitope. MolAspects Med 1991; 12: 283-96. Ann Rheum Dis: first published as 10.1136/ard.52.Suppl_1.S22 on 1 March 1993. Downloaded from 55 Schoel B, Gulle H, Kaufmann S H E. Heterogeneity of the 74 Kirchner H, Brehm G, Nicklas W, Beck R, Herbst F. repertoire of T cells of tuberculosis patients and healthy Biochemical characterisation of the T-cell mitogen contacts to Mycobacterium tuberculosis antigens derived from Mycoplasma arthritidis. Scand J Immunol separated by high-resolution techniques. Infect Immun 1986; 24: 245-9. 1992; 60: 1717-20. 75 Atkin C L, Cole B C, Sullivan G J, Washburn L R, Wiley 56 Haregewoin A, Soman G, Hom R C, Finberg R W. Human B B. Stimulation of mouse lymphocytes by a mitogen y5' T cells respond to mycobacterial heat-shock protein. derived from Mycoplasma Arthritidis. 7 Immunol 1986; Nature 1989; 340: 309-11. 137: 1581-9. 57 O'Brien R L, Happ M P, Dallas A, Palmer E, Kubo R, Born 76 Paliard X, West S G, Lafferty J A, et al. Evidence for the W K. Stimulating of a major subset of lymphocytes effects of a superantigen in rheumatoid arthritis. Science expressing T cell receptor -y by an antigen derived from 1991; 253: 325-9. mycobacterium tuberculosis. Cell 1989; 57: 667-74. 77 He X, Goronzy J, Weyand C. Selective induction of 58 O'Brien R L, Happ M P, Dallas A, et al. Recognition of a rheumatoid factors by superantigens and human helper T single hsp-60 epitope by an entire subset of yS T cells. J Clin Invest 1992; 89: 673-80. lymphocytes. Immunol Rev 1991; 121: 155-70. 78 Holoshitz J, Vila L M, Keroack B J, McKinley D R, Bayne 59 Born W, Hall L, Dallas A, et al. Recognition of a peptide N K. Dual antigenic recognition by cloned human y8 T antigen by heat shock-reactive y8 T lymphocytes. Science cells. Clin Invest 1990; 249: 67-9. J 1992; 89: 308-14. 60 Langer T, Neupert W. Heat shock proteins hsp60 and 79 Olive C, Gatenby P A, Serjeantson S W. Variable gene hsp70: their roles in folding, assembly and membrane usage of T cell receptor y- and b-chain transcripts translocation of proteins. Curr Top Microbiol Immunol expressed in synovia and peripheral blood of patients with 1991; 167:3-30. rheumatoid arthritis. Clin Exp Immunol 1992; 87: 172-7. 61 Koll H, Guiard B, Rassow J, et al. Antifolding activity of 80 Doherty P J, Yang S X, Laxer R M, Silverman E D, Inman hsp60 couples protein import into the mitochondrial R, Pan S. Evidence for clonal expansion of T cell receptor matrix with export to the intermembrane space. Cell 1992; V-yII+ T cells in the synovial fluid of patients with arthritis. 68: 1163-75. JlImmunol 1992; 149: 295-9. 62 Fisch P, Malkovsky M, Kovats S, et al. Recognition by 81 Kabelitz D, Bender A, Schondelmaier S, Schoel B, human V-yN82 T cells of a GroEL homolog on Daudi Kaufmann S H E. A large fraction of human peripheral Burkitt's lymphoma cells. Science 1990; 250: 1269-73. blood -y/8 T cells is activated by Mycobacterium 63 Rajagopalan S, Mao C, Datta S K. Pathogenic tuberculosis but not by its 65-kD heat shock protein. J autoantibody-inducing y/8 T helper cells from patients Exp Med 1990; 171: 667-79. with lupus nephritis express unusual T cell receptors. Clin 82 Orme I M, Miller E S, Roberts A D, et al. T lymphocytes Immunol Immunopathol 1992; 62: 344-50. mediating protection and cellular cytolysis during the 64 Holoshitz J, Koning F, Coligan J E, De Bruyn J, Strober course of Mycobacterium tuberculosis infection. S. Isolation of CD4- CD8- mycobacteria-reactive T Evidence for different kinetics and recognition of a wide lymphocyte clones from rheumatoid arthritis synovial spectrum of protein antigens. J Immunol 1992; 148: fluid. Nature 1989; 339: 226-9. 189-96. 65 van Eden W, Thole J E R, van der Zee R, et al. Cloning 83 Kabelitz D, Bender A, Prospero T, Wesselborg S, Janssen of the mycobacterial epitope recognized by T lymphocytes 0, Pechhold K. The primary response of human y/8' T in adjuvant arthritis. Nature 1988; 331: 171-3. cells to Mycobacterium tuberculosis is restricted to 66 Haregewoin A, Singh B, Gupta R S, Finberg R W. A Vy9-bearing cells. J ExpMed 1991; 173: 1331-8. mycobacterial heat-shock protein-responsive y8 T cell 84 Casorati G, de Libero G, Lanzavecchia A, Migone N. clone also responds to the homologous human heat-shock Molecular analysis of human y/8 clones from thymus and protein: a possible link between infection and peripheral blood. J Exp Med 1989; 170: 1521-30. autoimmunity. _lInfect Dis 1991; 163: 156-60. 85 Rust C J J, Verreck F, Vietor H, Koning F. Specific 67 Quayle A J, Black Wilson K, Le S G, et al. Peptide recognition of staphylococcal enterotoxin A by human T recognition, T cell receptor usage and HLA restriction cells bearing receptors with the Vy9 region. Nature 1990; elements of human heat-shock protein (hsp) 60 and 346: 572-4. mycobacterial 65-kDa hsp-reactive T cell clones from 86 Johnson H M, Russell J K, Pontzer C H. Staphylococcal rheumatoid synovial fluid. Eur J Immunol 1992; 22: enterotoxin microbial superantigens. FASEB J 1991; 5: 1315-22. 2706-12. 68 Crick F D, Gatenby P A. Limiting-dilution analysis of T 87 Pfeffer K, Schoel B, Plesnila N, et al. A lectin-binding, cell reactivity to mycobacterial antigens in peripheral protease-resistant mycobacterial ligand specifically blood and synovium from rheumatoid arthritis patients. activates Vy9+ human -yb T cells. J Immunol 1992; 148: Clin Exp Immunol 1992; 88: 424-9. 575-83.

69 Life P F, Bassey E 0 E, Hill Gaston J S. T-cell recognition 88 Correa I, Bix M, Liao N-S, Zijlstra M, Jaenisch R, Raulet http://ard.bmj.com/ of bacterial heat-shock proteins in inflammatory arthritis. D. Most -y8 T cells develop normally in 132-microglobulin- Immunol Rev 1991; 121: 113-35. deficient mice. Proc NatlAcad Sci USA 1992; 89: 653-7. 70 Res P C M, Telgt D, van Laar J M, Pool M 0, Breedveld 89 Pereira P, Zijlstra M, McMaster J, Loring J M, Jaenisch R, F C, de Vries R R P. High antigen reactivity in Tonegawa S. Blockade of transgenic lyS T cell mononuclear cells from sites of chronic inflammation. development in j32-microglobulin deficient mice. EMBO Lancet 1990; 336: 1406-8. J 1992; 11: 25-31. 71 Kaufmann S H E. Heat shock proteins and autoimmunity: 90 Vidovic D, Roglic M, McKune K, Guerder S, MacKay C, fact or fiction? The evidence from animal models Dembic Z. Qa-I restricted recognition of foreign antigen suggesting the involvement of heat shock protein I by a y8 T-cell hybridoma. Nature 1989; 340: 646-50. is supported by some, but not all, 91 Bucy R P, Chen C-L H, Cooper M D. Tissue localization data from autoimmune disease patients. Current Biology and CD8 accessory molecule expression of Ty8 cells in on October 1, 2021 by guest. Protected copyright. 1991; 1: 359-61. humans.JIImmunol 1989; 142: 3045-9. 72 Rippmann F, Taylor N R, Rothbard J B, Green N M. A 92 Christmas S E. Cytokine production by T lymphocytes hypothetical model for the peptide binding domain ofhsp bearing the gamma-delta T cell antigen receptor. Chem 70 based on the peptide binding domain of HLA. EMBO Immunol 1992; 53: 32-46. J 1991; 10: 1053-9. 93 Morita C T, Verma S, Aparicio P, Martinez-A C, Spits H, 73 Hounsell E F, Renouf D V, Liney D, Dalgleish A G, Brenner M B. Functionally distinct subsets of human -y/8 Habeshaw J. A proposed molecular model for the T cells. EurJtImmunol 1991; 21: 2999-3007.