Antigen processing and presentation of a naturally glycosylated protein elicits major histocompatibility complex class II‐restricted, carbohydrate‐specific T cells

Michaëlsson, Erik; Broddefalk, Johan; Engström, Åke; Kihlberg, Jan; Holmdahl, Rikard

doi:10.1002/eji.1830260835

Cited by 67 publications

(56 citation statements)

References 23 publications

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“…This T cell determinant contains lysine residues at position 264 and 270, which can become posttranslationally modified by hydroxylation and further galactosylated and glucosylated, creating many different epitopes containing hydroxyl, mono-and disaccharide groups in both RA and CIA. We have previously shown that autoreactive T cells predominantly recognize this epitope when it is posttranslationally modified at positions 264 and 270 by hydroxylation and further glycosylation [11][12][13]. The dominant T cell epitope is the side-chain of lysine at position 264 (K264) when the peptide is bound to A q , but when bound to DR4 the T cells recognize either position K264 or K270, although position 264 seems to be the more dominant of the two in this case.…”

Section: Introductionmentioning

confidence: 94%

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

et al. 2005

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Type II collagen (CII) is a target for autoreactive T cells in both rheumatoid arthritis and the murine model collagen-induced arthritis. The determinant core of CII has been identified as CII260-270, and the alteration of this T cell epitope by posttranslational modifications is known to be critical for development of arthritis in mice. Using CIIspecific T cell hybridomas we have now shown that the immunodominant T cell epitope in the normal (healthy) human and rat joint cartilage is O-glycosylated at the critical T cell receptor recognition position 264 with a mono-or di-saccharide attached to a hydroxylysine. In contrast, in the arthritic human and rat joint cartilage there are both glycosylated and non-glycosylated CII forms. Glycosylated CII from normal cartilage could not be recognized by T cells reactive to peptides having only lysine or hydroxylysine at position 264, showing that antigen-presenting cells could not degrade the O-linked carbohydrate. Thus, the variable forms of the glycosylated epitope are determined by the structures present in cartilage, and these vary during the disease course. We conclude that the chondrocyte determines the structures presented to the immune system and that these structures are different in normal versus arthritic states.

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Section: Introductionmentioning

confidence: 94%

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

et al. 2005

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“…We used an established system with mouse hybridoma T cells and spleen-derived antigen-presenting cells (APCs). HCQ10 T hybridoma cells (18), which recognize the immunodominant CII peptide bound to the class II molecule H2-A q , or APCs were treated with PBS or with 4 mM GSH to increase the number of cell surface ϪSH groups. Higher numbers of cell surface thiols on T cells were shown to increase IL-2 production, whereas a higher number of thiol groups on APCs did not (Fig.…”

Section: Increasing the Number Of Cell Surface ؊Sh Groups On T Cells mentioning

confidence: 99%

T cell surface redox levels determine T cell reactivity and arthritis susceptibility

Gelderman

Hultqvist

Holmberg

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

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Rats and mice with a lower capacity to produce reactive oxygen species (ROS) because of allelic polymorphisms in the Ncf1 gene (which encodes neutrophil cytosolic factor 1) are more susceptible to develop severe arthritis. These data suggest that ROS are involved in regulating the immune response. We now show that the lower capacity to produce ROS is associated with an increased number of reduced thiol groups (؊SH) on T cell membrane surfaces. Artificially increasing the number of reduced thiols on T cells from animals with arthritis-protective Ncf1 alleles by glutathione treatment lowered the threshold for T cell reactivity and enhanced proliferative responses in vitro and in vivo. Importantly, T cells from immunized congenic rats with an E3-derived Ncf1 allele (DA.Ncf1 E3 rats) that cannot transfer arthritis to rats with an arthritis-associated Dark Agouti (DA)-derived mutated Ncf1 allele (DA.Ncf1 DA rats) became arthritogenic after increasing cell surface thiol levels. This finding was confirmed by the reverse experiment, in which oxidized T cells from DA.Ncf1 DA rats induced less severe arthritis compared with controls. Therefore, we conclude that ROS production as controlled by Ncf1 is important in regulating surface redox levels of T cells and thereby suppresses autoreactivity and arthritis development.Ncf1 ͉ reactive oxidative species ͉ p47 phox ͉ NADPH ͉ glutathione R eactive oxygen species (ROS) are generally thought to be harmful and to play a disease-enhancing role in autoimmune diseases such as arthritis (1, 2). However, we have found that a decreased capacity to produce ROS because of polymorphisms in Ncf1 increases susceptibility for autoimmunity and arthritis (3, 4). Ncf1 encodes neutrophil cytosolic factor 1 (Ncf1, also known as p47phox), the activating protein in the NADPH oxidase complex that produces ROS upon activation. In the rat, a SNP in the Ncf1 gene was identified by positional cloning to be one of the strongest genes in regulating both oxidative burst and arthritis (3). In the mouse, a spontaneous mutation was identified that affects splicing and results in expression of truncated, less functional Ncf1 protein (5), which also resulted in increased arthritis and autoimmunity (4). Hence, it was clear that the Ncf1 gene that controls oxidative burst also controlled the autoimmune response and severity of arthritis in both rats and mice.It has been shown that arthritis as induced by immunization with pristane in rats and collagen in mice expressing polymorphic Ncf1 is T cell dependent. In the rat model, only T cells from DA.Ncf1 DA rats [Dark Agouti (DA) rats with the mutated Ncf1 DA allele from the DA rat] can transfer disease to naïve DA.Ncf1 DA recipients, whereas T cells from the congenic DA.Ncf1 E3 rats (DA rats with the WT Ncf1 E3 allele from the E3 rat) cannot (3, 6). In the mouse model, a mutation in Ncf1 results in an increased delayed-type hypersensitivity response and serum levels of anti-collagen type II (CII) IgG antibodies (4), indicating enhanced activation of autoreactive T ...

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“…We have previously shown the importance of galactosylation at position K 264 of CII259-273 for the immune recognition [12][13][14][15][16][17] and that CII in the healthy individuals is completely glycosylated at this position [16]. In line with these findings, an additional modification at position Q 267 by deamidation makes the study of the immune response more complex.…”

Section: Discussionmentioning

confidence: 54%

“…It is well established that during aging, inflammation, trauma or other pathologic processes, the frequency of posttranslational modifications, such as glycosylation, glycation, citrullination, oxidation, deamidation/transamidation or phosphorylation, is increased [10,11]. The role of glycosylated immunodominant CII260-270-peptide for development of autoimmune arthritis has been previously described [12][13][14][15][16][17].…”

Section: Introductionmentioning

confidence: 99%

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Tissue transglutaminase enhances collagen type II‐induced arthritis and modifies the immunodominant T‐cell epitope CII260‐270

Dzhambazov

Lindh

Engström³

et al. 2009

Eur J Immunol

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The calcium-dependent enzyme tissue transglutaminase (tTG) is associated with diverse biological functions, such as induction of apoptosis, modeling of the extracellular matrix, receptor-mediated endocytosis, cell growth and differentiation, cell adhesion and signal transduction. Also, it may deamidate glutamine residues to glutamic acid and catalyze cross-linking of proteins. In this study, we have investigated the impact of tTG for posttranslational modifications and cross-linking of the immunodominant T-cell epitope CII260-270 and their effects on the collagen-induced arthritis, an animal model for rheumatoid arthritis. By using mass spectrometry analysis and hybridoma assays, we have demonstrated that tTG could perform both types of modifications (deamidation and cross-link formation) on the immunodominant T-cell epitope CII259-273. Replacement of the glutamine at position 267 with glutamic acid leads to a decreased binding affinity to MHC II. T cells recognized both non-modfied (Q 267 ) and modified (E 267 ) CII259-273-peptides. We also show that administration of tTG leads to increased incidence, severity and histopathological manifestations of collagen-induced arthritis in mice. Moreover, we conclude that both processes, deamidation and cross-linking, are involved in the tTG-catalyzed reactions, and in vivo administration of tTG enhances arthritis severity and joint destruction in mice.Key words: Collagen-induced arthritis . CII-peptide . Posttranslational modifications .T cells . Tissue transglutaminase IntroductionPosttranslational modifications of proteins are being recognized as increasingly important for the initiation and pathogenesis of autoimmune diseases. Such modifications could lead to breaking of the immunological tolerance to self proteins by creation of new epitopes within the target antigen. Rheumatoid arthritis (RA) is an autoimmune disease involving an inflammatory attack on peripheral cartilaginous joints characterized by leukocyte infiltration, secretion of inflammatory cytokines and auto-Ab, and subsequent cartilage destruction, irreversible bone erosion and joint deformation. Major candidate autoantigens in RA that are locally expressed in the joint are type II collagen (CII), fibrin, and proteoglycans. CII is of particular interest, since T-and B-cell autoimmune responses to this protein leads to collagen-induced arthritis (CIA) in mice [1], rats [2] and primates [3,4], which shares many phenotypic features with RA. The shared immunodominant T-cell epitope in CIA and RA has been identified as . Amino acids of this immunodominant core can be posttranslationally modified either by enzymatic processes or spontaneously. It is well established that during aging, inflammation, trauma or other pathologic processes, the frequency of posttranslational modifications, such as glycosylation, glycation, citrullination, oxidation, deamidation/transamidation or 2412phosphorylation, is increased [10,11]. The role of glycosylated immunodominant CII260-270-peptide for development of autoimmune arthri...

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Antigen processing and presentation of a naturally glycosylated protein elicits major histocompatibility complex class II‐restricted, carbohydrate‐specific T cells

Cited by 67 publications

References 23 publications

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

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

T cell surface redox levels determine T cell reactivity and arthritis susceptibility

Tissue transglutaminase enhances collagen type II‐induced arthritis and modifies the immunodominant T‐cell epitope CII260‐270

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