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

Malcolm, J.; Nyirenda, M. H.; Brown, J. L.; Adrados-Planell, A.; Campbell, L.; Butcher, J. P.; Glass, D. G.; Piela, K.; Goodyear, C. S.; Wright, A. J.; McInnes, I. B.; Millington, O. R.; Culshaw, S.

Abstract

In rheumatoid arthritis, the emergence of anti-citrullinated autoimmunity is associated with HLA-antigen-T cell receptor complexes. The precise mechanisms underpinning this breach of tolerance are not well understood. Porphyromonas gingivalis expresses an enzyme capable of non-endogenous C-terminal citrullination with potential to generate citrullinated autoantigens. Here we document how C-terminal citrullination of ovalbumin peptide323-339 alters the interaction between antigen-presenting cells and OTII T cells to induce functional changes in responding T cells. These 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. Finally, we demonstrate a role for the IL-2/STAT5/CD25 signalling axis in breach of tolerance. Together, our data identify a tractable mechanism and targetable pathways underpinning breach of tolerance in rheumatoid arthritis and provide new conceptual insight into the origins of anti-citrullinated autoimmunity.

Citation

Malcolm, J., Nyirenda, M. H., Brown, J. L., Adrados-Planell, A., Campbell, L., Butcher, J. P., …Culshaw, S. (2023). C-terminal citrullinated peptide alters antigen-specific APC:T cell interactions leading to breach of immune tolerance. Journal of Autoimmunity, 135, Article 102994. https://doi.org/10.1016/j.jaut.2023.102994

• Journal Article Type: Article
• Acceptance Date: Jan 5, 2023
• Online Publication Date: Jan 25, 2023
• Publication Date: Feb 1, 2023
• Deposit Date: Apr 18, 2023
• Publicly Available Date: Apr 18, 2023
• Journal: Journal of Autoimmunity
• Print ISSN: 0896-8411
• Electronic ISSN: 1095-9157
• Publisher: Elsevier
• Peer Reviewed: Peer Reviewed
• Volume: 135
• Article Number: 102994
• DOI: https://doi.org/10.1016/j.jaut.2023.102994
• Keywords: Immunology; Immunology and Allergy
• Public URL: https://nottingham-repository.worktribe.com/output/16789928
• Publisher URL: https://www.sciencedirect.com/science/article/pii/S0896841123000033?via%3Dihub