scholarly journals 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

2022 ◽  
pp. annrheumdis-2021-220500
Author(s):  
Changrong Ge ◽  
Sylvia Weisse ◽  
Bingze Xu ◽  
Doreen Dobritzsch ◽  
Johan Viljanen ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
T Cells ◽  
T Cell ◽  
Crystal Structures ◽  
T Cell Receptor ◽  
Mhc Class Ii ◽  
Mononuclear Cells ◽  
Lentiviral Vector ◽  
Dominant Role ◽  
Cell Receptor

ObjectivesRheumatoid 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.MethodsThe 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.ResultsThe 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.ConclusionsThe 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.

Dominant and Shared T Cell Receptor β Chain Variable Regions of T Cells Inducing Synovial Hyperplasia in Rheumatoid Arthritis

1999 ◽  
Vol 263 (1) ◽  
pp. 172-180 ◽  
Author(s):  
Toru Mima ◽  
Shiro Ohshima ◽  
Mitsuko Sasai ◽  
Katsuhiro Nishioka ◽  
Masatoshi Shimizu ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
T Cells ◽  
T Cell ◽  
T Cell Receptor ◽  
Cell Receptor ◽  
Variable Regions ◽  
Synovial Hyperplasia ◽  
Β Chain

scholarly journals TCR repertoire analysis reveals effector memory T cells differentiation into Th17 cells in rheumatoid arthritis

2019 ◽  
Author(s):  
Xu Jiang ◽  
Shi-yu Wang ◽  
Chen Zhou ◽  
Jing-hua Wu ◽  
Yu-hao Jiao ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
T Cells ◽  
T Cell ◽  
T Cell Receptor ◽  
Th17 Cells ◽  
Cell Receptor ◽  
T Cell Subsets ◽  
Effector Memory ◽  
Systemic Autoimmune Disease ◽  
Autoreactive T Cell

AbstractThe pathogenesis of rheumatoid arthritis (RA), a systemic autoimmune disease characterized by autoreactive T-cell accumulation and pro-inflammatory cytokine overproduction, is unclear. Systematically addressing T-cell receptor (TCR) repertoires of different CD4+ T-cell subsets could help understand RA pathogenesis. Here, peripheral CD4+ T cells from treatment-naïve RA patients and healthy controls were sorted into seven subsets including naïve, effector, central memory, effector memory (EMT), Th1, Th17, and regulatory T cells. T-cell receptor β chain repertoires were then analyzed by next-generation sequencing. We identified T-cell clonal expansion in EMT and Th17 cells, with highly similar TCR repertoires between them. Ex vivo experiments demonstrated the preferred differentiation from EMT to Th17 cells in RA. Moreover, TCR diversity in subsets including Th17 was negatively correlated with RA disease activity indices such as C-reactive protein and erythrocyte sedimentation rate. Thus, shared and abnormally expanded EMT and Th17 TCR repertoires might be pivotal for RA pathogenesis.

CDR3 Length Restriction of T-Cell Receptor ? Chains in CD8+ T-Cells of Rheumatoid Arthritis Patients

1995 ◽  
Vol 756 (1 T-Cell Recept) ◽  
pp. 179-182 ◽  
Author(s):  
R. HINGORANI ◽  
J. MONTEIRO ◽  
R. PERGOLIZZI ◽  
R. FURIE ◽  
E. CHARTASH ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
T Cells ◽  
T Cell ◽  
T Cell Receptor ◽  
Cd8 T Cells ◽  
Cell Receptor ◽  
Cdr3 Length

scholarly journals Biased t cell receptor v gene usage in rheumatoid arthritis. oligoclonal expansion of t cells expressing vα2 genes in synovial fluid but not in peripheral blood

1993 ◽  
Vol 36 (9) ◽  
pp. 1234-1243 ◽  
Author(s):  
Barbara M. Bröker ◽  
Ulf Korthäuer ◽  
Peter Heppt ◽  
Gerd Weseloh ◽  
RÜDiger De La Camp ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
T Cells ◽  
T Cell ◽  
Synovial Fluid ◽  
T Cell Receptor ◽  
Peripheral Blood ◽  
Cell Receptor ◽  
Gene Usage ◽  
V Gene ◽  
Oligoclonal Expansion

scholarly journals Pathogenesis of an Infectious Mononucleosis-like Disease Induced by a Murine γ-Herpesvirus: Role for a Viral Superantigen?

1997 ◽  
Vol 185 (9) ◽  
pp. 1641-1650 ◽  
Author(s):  
Ralph A. Tripp ◽  
Ann Marie Hamilton-Easton ◽  
Rhonda D. Cardin ◽  
Phuong Nguyen ◽  
Frederick G. Behm ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Receptor ◽  
Mhc Class Ii ◽  
Infectious Mononucleosis ◽  
Cd8 T Cells ◽  
Peripheral Blood ◽  
Cell Receptor ◽  
Class Ii ◽  
Congenic Mice

The murine γ-herpesvirus 68 has many similarities to EBV, and induces a syndrome comparable to infectious mononucleosis (IM). The frequency of activated CD8+ T cells (CD62Llo) in the peripheral blood increased greater than fourfold by 21 d after infection of C57BL/6J (H-2b) mice, and remained high for at least a further month. The spectrum of T cell receptor usage was greatly skewed, with as many as 75% of the CD8+ T cells in the blood expressing a Vβ4+ phenotype. Interestingly, the Vβ4 dominance was also seen, to varying extents, in H-2k, H-2d, H-2u, and H-2q strains of mice. In addition, although CD4 depletion from day 11 had no effect on the Vβ4 bias of the T cells, the Vβ4+CD8+ expansion was absent in H-2IAb–deficient congenic mice. However, the numbers of cycling cells in the CD4 antibody–depleted mice and mice that are CD4 deficient as a consequence of the deletion of MHC class II, were generally lower. The findings suggest that the IM-like disease is driven both by cytokines provided by CD4+ T cells and by a viral superantigen presented by MHC class II glycoproteins to Vβ4+CD8+ T cells.

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