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Key interactions in...
Key interactions in the trimolecular complex consisting of the rheumatoid arthritis-associated DRB1*04:01 molecule, the major glycosylated collagen II peptide and the T-cell receptor
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- Ge, Changrong (author)
- Karolinska Institutet
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- Weisse, Sylvia (author)
- Fraunhofer Inst Translat Med & Pharmacol ITMP, Frankfurt, Germany
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- Xu, Bingze (author)
- Karolinska Inst, Sect Med Inflammat Res, Dept Med Biochem & Biophys, Stockholm, Sweden
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- Dobritzsch, Doreen, 1972- (author)
- Uppsala universitet,Biokemi
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- Viljanen, Johan V. (author)
- Uppsala universitet,Organisk kemi
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- Kihlberg, Jan (author)
- Uppsala universitet,Organisk kemi
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- Do, Nhu-Nguyen (author)
- Karolinska Inst, Sect Med Inflammat Res, Dept Med Biochem & Biophys, Stockholm, Sweden.;Fraunhofer Inst Translat Med & Pharmacol ITMP, Frankfurt, Germany
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- Schneider, Nadine (author)
- Fraunhofer Inst Translat Med & Pharmacol ITMP, Frankfurt, Germany
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- Lanig, Harald (author)
- Friedrich Alexander Univ Erlangen Nurnberg, Cent Inst Sci Comp ZISC, Erlangen, Germany.;Friedrich Alexander Univ Erlangen Nurnberg, Erlangen Natl High Performance Comp Ctr, Erlangen, Germany
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- Holmdahl, Rikard (author)
- Karolinska Institutet
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- Burkhardt, Harald (author)
- Fraunhofer Inst Translat Med & Pharmacol ITMP, Frankfurt, Germany.;Fraunhofer Cluster Excellence Immune Mediated Dis, Frankfurt, Germany.;Goethe Univ, Univ Hosp Frankfurt, Div Rheumatol, Frankfurt, Germany
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(creator_code:org_t)
- 2022-01-13
- 2022
- English.
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In: Annals of the Rheumatic Diseases. - : BMJ Publishing Group Ltd. - 0003-4967 .- 1468-2060. ; 81:4, s. 480-489
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Abstract
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- Objectives Rheumatoid arthritis (RA) is an autoimmune disease strongly associated with the major histocompatibility complex (MHC) class II allele DRB1*04:01, which encodes a protein that binds self-peptides for presentation to T cells. This study characterises the autoantigen-presenting function of DRB1*04:01 (HLA-DRA*01:01/HLA-DRB1*04:01) at a molecular level for prototypic T-cell determinants, focusing on a post-translationally modified collagen type II (Col2)-derived peptide.Methods The crystal structures of DRB1*04:01 molecules in complex with the peptides HSP70(289-306), citrullinated CILP982-996 and galactosylated Col2(259-273) were determined on cocrystallisation. T cells specific for Col2(259-273) were investigated in peripheral blood mononuclear cells from patients with DRB1*04:01-positive RA by cytofluorometric detection of the activation marker CD154 on peptide stimulation and binding of fluorescent DRB1*0401/Col2(259-273) tetramer complexes. The cDNAs encoding the T-cell receptor (TCR) alpha-chains and beta-chains were cloned from single-cell sorted tetramer-positive T cells and transferred via a lentiviral vector into TCR-deficient Jurkat 76 cells.Results The crystal structures identified peptide binding to DRB1*04:01 and potential side chain exposure to T cells. The main TCR recognition sites in Col2(259-273) were lysine residues that can be galactosylated. RA T-cell responses to DRB1*04:01-presented Col2(259-273) were dependent on peptide galactosylation at lysine 264. Dynamic molecular modelling of a functionally characterised Col2(259-273)-specific TCR complexed with DRB1*04:01/Col2(259-273) provided evidence for differential allosteric T-cell recognition of glycosylated lysine 264.Conclusions The MHC-peptide-TCR interactions elucidated in our study provide new molecular insights into recognition of a post-translationally modified RA T-cell determinant with a known dominant role in arthritogenic and tolerogenic responses in murine Col2-induced arthritis.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Immunologi inom det medicinska området (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Immunology in the medical area (hsv//eng)
Keyword
- rheumatoid arthritis
- autoimmunity
- T-lymphocyte subsets
Publication and Content Type
- ref (subject category)
- art (subject category)
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Ge, Changrong
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Weisse, Sylvia
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Xu, Bingze
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Dobritzsch, Dore ...
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Viljanen, Johan ...
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Kihlberg, Jan
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Do, Nhu-Nguyen
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Schneider, Nadin ...
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Lanig, Harald
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Holmdahl, Rikard
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Burkhardt, Haral ...
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Basic Medicine
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and Immunology in th ...
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Annals of the Rh ...
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Uppsala University
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Karolinska Institutet