Purpose: Rheumatoid arthritis (RA) is an autoimmune disease closely related to the major histocompatibility complex (MHC) class II allele DRB1*04:01 , which encodes a combination of Self-peptide as a protein presented to T cells
.
This study characterizes the autoantigen-presenting function of DRB1*04:01 (HLA-DRA*01:01/HLA-DRB1*04:01) at the molecular level of prototypic T- cell determinants , focusing on post-translationally modified collagen Type II (Col2) derived peptides .
Objective: Rheumatoid Arthritis Rheumatoid arthritis (RA) is an autoimmune disease closely related to the major histocompatibility complex immune (MHC) class II allele DRB1*04:01 .
The allele encodes a protein that binds to a self-peptide for presentation to T cells
.
This study characterizes the autoantigen-presenting function of DRB1*04:01 (HLA-DRA*01:01/HLA-DRB1*04:01) at the molecular level of prototypic T- cell determinants , focusing on post-translationally modified collagen Type II (Col2) derived peptides .
Methods: The crystal structure of the DRB1*04:01 molecule in complex with the peptides HSP70 289-306 , citrullinated CILP 982-996 and galactosylated Col2 259-273 was determined by co-crystallization .
The effect of Col2 259 was investigated in peripheral blood mononuclear cells from DRB1*04:01 -positive RA patients by cytofluorimetric detection of activation-labeled CD154 upon peptide stimulation and binding of the fluorescent DRB1*0401/Col2 259-273 tetrameric complex.
-273 -specific T cells .
cDNAs encoding T cell receptor (TCR) alpha and beta chains were cloned from single-cell sorted tetramer-positive T cells and transferred into TCR -deficient Jurkat 76 cells by lentiviral vector .
Methods: The crystal structure of the DRB1*04:01 molecule complexed with the peptides HSP70 289-306 289-306 , citrullinated CILP 982-996 982-996 and galactosylated Col2 259-273 259-273 was determined by co-crystallization .
studied in peripheral blood mononuclear cells from DRB1*04:01 -positive RA patients by cytofluorimetric detection of activation-labeled CD154 bound by peptide stimulation and fluorescent DRB1*0401/Col2 259-273 259-273 tetrameric complexes T cells specific for Col2 259-273 259-273 .
cDNAs encoding T cell receptor (TCR) alpha and beta chains were cloned from single-cell sorted tetramer-positive T cells and transferred by lentiviral vectors to
in TCR -deficient Jurkat 76 cells
.
Results: The crystal structure identified a peptide bound to DRB1*04:01 and a potential side chain exposed to T cells .
The major TCR recognition sites in Col2 259-273 are lysine residues that can be galactosylated .
RA T cell response to Col2 259-273 presented by DRB1*04:01 depends on peptide galactosylation at lysine 264 .
A dynamic molecular model of a functionally characterized Col2 259-273 -specific TCR provides evidence for differential allosteric T cell recognition of glycosylated lysine 264 in complex with DRB1*04:01/Col2 259-273 .
Results: The crystal structure identified a peptide bound to DRB1*04:01 and a potential side chain exposed to T cells .
The major TCR recognition site in Col2 259-273 259-273 is a lysine residue that can be galactosylated .
Response of RA T cells to Col2 259-273 259-273 presented by DRB1*04:01 depends on peptide galactosylation at lysine 264 .
A dynamic molecular model of functionally characterized Col2 259-273 259-273 -specific TCR provides differential allosteric T cell recognition of glycosylated lysine 264 complexed with DRB1*04:01/Col2 259-273 259-273 evidence .
Conclusions: This study provides new crystal structure information revealing the function of DRB1*04:01 in presenting post-translationally modified epitopes to T cells of RA patients .
A comparative analysis of molecular modeling of RA T cells, T cell receptor (TCR) clones, and a prototypical trimolecular complex provides insight into TCR recognition of unmodified and glycosylated Col2 in the context of DRB1*04:01 .
MHC- peptide - TCR interactions provide new molecular insights into the identification of post-translationally modified RA T- cell determinants with known major roles in arthritogenic and tolerogenic responses to Col2 -induced arthritis in mice role .
Conclusions: This study provides new crystal structure information revealing the function of DRB1*04:01 in presenting post-translationally modified epitopes to T cells of RA patients .
A comparative analysis of molecular modeling of RA T cells, T cell receptor (TCR) clones, and a prototypical trimolecular complex provides insight into TCR recognition of unmodified and glycosylated Col2 in the context of DRB1*04:01 .
MHC- peptide - TCR interactions provide new molecular insights into the identification of post-translationally modified RA T- cell determinants with known major roles in arthritogenic and tolerogenic responses to Col2 -induced arthritis in mice role .
Source:
Ge C, Weisse S, Xu B , et al .
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 2022; 81: 480-489.
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 2022; 81: 480-489.
, et al Annals of the Rheumatic Diseases 81:
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