The DOI matches its Crossref record; 41 of the 41 references it cites were found in a registry or an index.
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
Abstract
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 HSP70289-306, citrullinated CILP982-996 and galactosylated Col2259-273 were determined on cocrystallisation. T cells specific for Col2259-273 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/Col2259-273 tetramer complexes. The cDNAs encoding the T-cell receptor (TCR) α-chains and β-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 Col2259-273 were lysine residues that can be galactosylated. RA T-cell responses to DRB1*04:01-presented Col2259-273 were dependent on peptide galactosylation at lysine 264. Dynamic molecular modelling of a functionally characterised Col2259-273-specific TCR complexed with DRB1*04:01/Col2259-273 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.
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Cites
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Genetics of rheumatoid arthritis contributes to biology and drug discovery
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Self-citationMixed lymphocyte cultures in rheumatoid arthritis.
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Type II Collagen Autoimmunity in Animals and Provocations Leading to Arthritis
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Self-citationHumoral immune response to citrullinated collagen type II determinants in early rheumatoid arthritis
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Self-citationRosloniec, E. F., Brand, D. D., Myers, L. K., Whittington, K. B., Gumanovskaya, M. L., Zaller, D. M., Woods, A., Altmann, D. M., Stuart, J. M., & Kang, A. H. (1997) · The Journal of Experimental Medicine · doi:10.1084/jem.185.6.1113 · Cited by 222
Metadata
- Authors
- Ge, C., Weisse, S., Xu, B., Dobritzsch, D., Viljanen, J., Kihlberg, J., Do, N.-N., Schneider, N., Lanig, H., Holmdahl, R., & Burkhardt, H.
- Venue
- Annals of the Rheumatic Diseases
- Publisher
- Elsevier BV
- Published
- 2022-04
- Volume
- 81
- Issue
- 4
- Pages
- 480-489
- ISSN
- 0003-4967
- Cited by
- 26
- References
- 41
- Language
- en
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- creativecommons.org/licenses/by-nc/4.0/ (vor)
- Funders
- Swedish Association against Rheumatism (R-757331)
- The Swedish Research Council (2015-02662 and 2017-06104)
- Federal State of Hesse (LOEWE-project 13, IME Fraunhofer Project Group TMP)
- German Federal Ministry of Education and Research (GO-Bio-project aidCURE; 031A385)
- Knut and Alice Wallenberg Foundation (KAW 2015.0063)
- Erling Persson Foundation (None)
- European Union Innovative Medicine Initiative project BeTheCure (115142)
- Fraunhofer Cluster of Excellence for Immune-mediated Diseases CIMD (none)
- Swedish Foundation for Strategic Research (RB13-0156)
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- Ge, C., Weisse, S., Xu, B., Dobritzsch, D., Viljanen, J., Kihlberg, J., Do, N.-N., Schneider, N., Lanig, H., Holmdahl, R., & Burkhardt, H. (2022). 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. Annals of the Rheumatic Diseases. https://doi.org/10.1136/annrheumdis-2021-220500
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