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

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

Research output: Contribution to journalArticlepeer-review

3 Citations (Scopus)
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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.
Original languageEnglish
Article number102994
Number of pages14
JournalJournal of Autoimmunity
Volume135
Early online date25 Jan 2023
DOIs
Publication statusPublished - 28 Feb 2023

Keywords

  • C-terminal citrullinated peptide
  • antigen-specific OTII T cells
  • OTII T cells
  • C-terminal citrullination
  • T cell activation
  • rheumatoid arthritis

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