In:
Annals of the Rheumatic Diseases, BMJ, Vol. 81, No. 4 ( 2022-04), p. 480-489
Kurzfassung:
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 CILP 982-996 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) 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 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.
Materialart:
Online-Ressource
ISSN:
0003-4967
,
1468-2060
DOI:
10.1136/annrheumdis-2021-220500
Sprache:
Englisch
Verlag:
BMJ
Publikationsdatum:
2022
ZDB Id:
1481557-6
