Citrullinated peptide-MHC class II-TCR complex (Cit-pMHCII-TCR)

The citrullinated peptide–MHC class II–TCR complex is a trimolecular assembly that plays a pivotal role in the initiation and progression of rheumatoid arthritis (RA) (Source 1.3.4). This complex forms when proteins such as vimentin, fibrinogen, or collagen undergo citrullination—a post-translational modification where arginine is converted to citrulline by peptidylarginine deiminase (PAD) enzymes—and are subsequently presented by MHC class II molecules, particularly those with the HLA-DRB1 "shared epitope" (Source 1.5.2, 1.5.5). Recognition of this complex by specific CD4+ T-cell receptors (TCRs) triggers the activation of autoreactive T cells, leading to the production of anti-citrullinated protein antibodies (ACPAs) and chronic synovial inflammation (Source 1.3.2, 1.5.3). In healthy individuals, these complexes typically induce immune tolerance, but in RA, a breach of this tolerance results in a pathogenic immune response (Source 1.2.3, 1.3.1). Therapeutic strategies targeting this interaction, such as the liposomal peptide formulation DEN-181 or dendritic cell-based vaccines like Rheumavax, aim to restore antigen-specific tolerance by inducing regulatory T cells or T-cell exhaustion (Source 1.3.1, 1.4.1). Additionally, these complexes are being explored as tumor-specific neoantigens in cancer immunotherapy, where they can be targeted to elicit potent anti-tumor T-cell responses in stressed or inflamed tumor microenvironments (Source 1.1.1, 1.2.2).

Other names

Citrullinated peptide-HLA-DR-TCR complexCit-peptide-MHCII-TCR complexCitrullinated neoantigen-MHCII complexCit-pMHC-TCR complex

Induction of antigen-specific immune tolerance through the expansion of regulatory T cells or the induction of T-cell anergy and exhaustion.