C-terminal citrullinated peptide alters APC-CD4 T cell interactions leading to breach of immune tolerance

Patients with rheumatoid arthritis harbour autoreactive T and B cells that target self-proteins containing a post-translational modification known as citrullination. This physiological modification regulates the structure and function of numerous proteins, and in health is not overtly immunogenic. Autoimmunity to citrullinated self-epitopes is associated with the interaction between certain HLA-alleles with environmental insults, such as smoking or microbial dysbiosis, at mucosal surfaces. However, the molecular mechanisms leading to the activation of autoreactive T and B lymphocytes in patients with RA remain ill-defined. Porphyromonas gingivalis is an immune subversive oral pathogen associated with microbial dysbiosis and chronic inflammation of oral gingival tissues. P. gingivalis expresses an enzyme capable of non-endogenous C-terminal citrullination. Using a synthetically generated C-terminally citrullinated model antigen (peptide ovalbumin), we demonstrate that this modification alters the interaction between antigen-presenting cells and OTII T cells to induce functional changes in responding T cells. Our data reveal that C-terminal citrullination is sufficient to breach T cell peripheral tolerance in vivo and reveal the potential of C-terminal citrullination to lower the threshold for T cell activation. Together, our data reveal a novel mechanism demonstrating how non-endogenous C-terminal citrullination can activate peripherally tolerised T cells to target native antigens.