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

Malcolm, J. and Nyirenda, M.H. and Brown, J.L. and Adrados-Planell, A. and Campbell, L. and Butcher, J.P. and Glass, D.G. and Piela, K. and Goodyear, C.S. and Wright, A.J. and McInnes, I.B. and Millington, O.R. and Culshaw, S. (2023) C-terminal citrullinated peptide alters antigen-specific APC:T cell interactions leading to breach of immune tolerance. Journal of Autoimmunity, 135. 102994. ISSN 0896-8411 (https://doi.org/10.1016/j.jaut.2023.102994)

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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.

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