HLA-DRB1*04:01-restricted collagen II-specific T-cell receptor (HLA-DRB1*04:01/CII TCR)

The HLA-DRB1*04:01-restricted collagen II-specific T-cell receptor (TCR) is a critical molecular mediator in the pathogenesis of rheumatoid arthritis (RA). This receptor specifically recognizes an immunodominant peptide derived from type II collagen (CII), typically residues 259-273 or 261-273, when presented by the MHC class II molecule HLA-DRB1*04:01. This recognition event forms a trimolecular complex that triggers the activation and expansion of autoreactive CD4+ T cells, which subsequently migrate to the synovial joints and orchestrate a chronic inflammatory response leading to cartilage and bone destruction. Therapeutic strategies targeting this TCR or its interaction with the MHC-peptide complex aim to restore immune tolerance or inhibit pathogenic T-cell signaling. Current approaches include the use of Abatacept to block costimulatory signals required for T-cell activation, as well as experimental therapies like DEN-181, a tolerogenic liposomal vaccine containing the CII peptide. Research also highlights the importance of post-translational modifications, such as the galactosylation of lysine 264 in the collagen peptide, which significantly enhances TCR binding and the resulting autoimmune response in patients carrying the RA-associated shared epitope alleles.

Other names

Collagen II-specific T-cell receptorDR4-restricted CII TCRHLA-DRB1*04:01/CII(259-273) TCRTRBV25-containing T-cell receptorTRBV6-4-containing T-cell receptorBV11-containing T-cell receptorBV13-containing T-cell receptor

Inhibition of T-cell activation, induction of immune tolerance (anergy or regulatory T-cell induction), and blocking of the MHC-peptide-TCR trimolecular complex formation.