Autoreactive T-cell receptor (HLA-DRB4-restricted)

The autoreactive T-cell receptor (TCR) recognizing disease-specific peptide–HLA-DRB4*01:01/*01:03 complexes is a specialized immune receptor that plays a pivotal role in the pathogenesis of autoimmune diseases, most notably Rheumatoid Arthritis (RA) (Scally et al., 2013, J. Immunol.). These TCRs are expressed on the surface of CD4+ T-helper cells and are characterized by their high affinity for self-antigens, such as citrullinated vimentin or fibrinogen, when presented by the HLA-DRB4 MHC class II molecule (James et al., 2014, JCI). The HLA-DRB4*01:01 allele is a significant genetic risk factor for RA, and its interaction with these TCRs triggers the activation of pathogenic T cells and the subsequent release of pro-inflammatory cytokines like IFN-gamma and IL-17 (Uniprot P13762). This recognition event is a critical upstream step in the inflammatory cascade that leads to joint destruction and systemic autoimmunity. Therapeutic strategies targeting these specific TCRs or their corresponding peptide-MHC complexes aim to restore immune tolerance through mechanisms such as the induction of T-cell anergy or the expansion of regulatory T cells (Tregs). Experimental modalities currently under investigation include peptide-MHC nanoparticles (Navacims), tolerogenic vaccines, and TCR-like antibodies designed to selectively modulate the immune response. By focusing on these specific autoreactive clones, these therapies seek to provide a more precise alternative to broad-spectrum immunosuppressants, potentially reducing side effects and improving patient outcomes.

Other names

HLA-DRB4-restricted TCRAutoreactive CD4+ TCRCitrulline-specific T-cell receptorRA-associated TCRHLA-DR53-restricted TCR

Induction of antigen-specific immune tolerance, selective depletion of autoreactive T-cells, or TCR-pMHC antagonism to prevent T-cell activation.