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  • Ge, ChangrongKarolinska Institutet (författare)

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

  • Artikel/kapitelEngelska2022

Förlag, utgivningsår, omfång ...

  • 2022-01-13
  • BMJ Publishing Group Ltd,2022
  • electronicrdacarrier

Nummerbeteckningar

  • LIBRIS-ID:oai:DiVA.org:uu-484551
  • https://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-484551URI
  • https://doi.org/10.1136/annrheumdis-2021-220500DOI
  • http://kipublications.ki.se/Default.aspx?queryparsed=id:148641273URI

Kompletterande språkuppgifter

  • Språk:engelska
  • Sammanfattning på:engelska

Ingår i deldatabas

Klassifikation

  • Ämneskategori:ref swepub-contenttype
  • Ämneskategori:art swepub-publicationtype

Anmärkningar

  • 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.

Ämnesord och genrebeteckningar

Biuppslag (personer, institutioner, konferenser, titlar ...)

  • Weisse, SylviaFraunhofer Inst Translat Med & Pharmacol ITMP, Frankfurt, Germany (författare)
  • Xu, BingzeKarolinska Inst, Sect Med Inflammat Res, Dept Med Biochem & Biophys, Stockholm, Sweden (författare)
  • Dobritzsch, Doreen,1972-Uppsala universitet,Biokemi(Swepub:uu)dordo526 (författare)
  • Viljanen, Johan V.Uppsala universitet,Organisk kemi(Swepub:uu)johvi609 (författare)
  • Kihlberg, JanUppsala universitet,Organisk kemi(Swepub:uu)janki643 (författare)
  • Do, Nhu-NguyenKarolinska Inst, Sect Med Inflammat Res, Dept Med Biochem & Biophys, Stockholm, Sweden.;Fraunhofer Inst Translat Med & Pharmacol ITMP, Frankfurt, Germany (författare)
  • Schneider, NadineFraunhofer Inst Translat Med & Pharmacol ITMP, Frankfurt, Germany (författare)
  • Lanig, HaraldFriedrich Alexander Univ Erlangen Nurnberg, Cent Inst Sci Comp ZISC, Erlangen, Germany.;Friedrich Alexander Univ Erlangen Nurnberg, Erlangen Natl High Performance Comp Ctr, Erlangen, Germany (författare)
  • Holmdahl, RikardKarolinska Institutet (författare)
  • Burkhardt, HaraldFraunhofer Inst Translat Med & Pharmacol ITMP, Frankfurt, Germany.;Fraunhofer Cluster Excellence Immune Mediated Dis, Frankfurt, Germany.;Goethe Univ, Univ Hosp Frankfurt, Div Rheumatol, Frankfurt, Germany (författare)
  • Karolinska InstitutetFraunhofer Inst Translat Med & Pharmacol ITMP, Frankfurt, Germany (creator_code:org_t)

Sammanhörande titlar

  • Ingår i:Annals of the Rheumatic Diseases: BMJ Publishing Group Ltd81:4, s. 480-4890003-49671468-2060

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