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Lookup NU author(s): Dr James Stanway, Dr Daniel PetersORCiD, Dr Helen WallerORCiD, Emeritus Professor Jeremy LakeyORCiD, Dr Henrique De Paula LemosORCiD, Dr Kristian Williams, Abbie Degnan, Julie Diboll, Dr Arthur PrattORCiD, Professor Catharien HilkensORCiD, Dr Amy AndersonORCiD, Professor John IsaacsORCiD
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
© 2026 The Author(s). Arthritis & Rheumatology published by Wiley Periodicals LLC on behalf of American College of Rheumatology.Objective: CD4 T cells specific for citrullinated (cit) peptides are key players in rheumatoid arthritis (RA) immunopathogenesis. Characterizing these cells and identifying features of healthy and RA-associated autoreactivity will provide valuable insight into disease mechanisms and form the basis of immune state biomarkers to facilitate the next generation of RA treatments. We sought to characterize these cells in a UK early arthritis cohort. Methods: Cit-peptide–specific (autoreactive) CD4 T cells from human leukocyte antigen (HLA)-DRB1 04:01–positive healthy controls (HCs; n = 9), patients with RA at different disease stages (n = 17 pretreatment and 13 receiving treatment), and six at-risk individuals were assessed using major histocompatibility complex II peptide tetramers combined with spectral flow cytometry. Autoreactive T cell frequency and phenotype were studied, with a particular focus on the memory CD4 T cell compartment. Results: There was no statistically significant difference in autoreactive T cell frequency between comparator groups. In HCs, however, autoreactive T cells were more likely to be naive. In early pretreatment RA, autoreactive memory T cells demonstrated down-regulation of CD27 and CD28 and expression of the fractalkine receptor CX3CR1, features that have been linked to CD4 cytotoxicity. The proportion of CD27-negative autoreactive cells decreased following treatment, and RA-associated features were evident in some at-risk donors before RA onset. Conclusion: In RA, CD4 T cell autoreactivity is characterized by a surface phenotype that suggests in vivo activation and the potential to acquire cytotoxic capacity, whereas healthy autoreactivity demonstrates naivety. These observations suggest maturing autoreactivity in RA and may provide novel tools for monitoring disease progression and tolerance.
Author(s): Stanway JA, Peters D, Waller H, Lakey J, Lemos HDP, Williams K, Degnan A, Diboll J, Baru AM, Tough D, Pratt AG, Hilkens CMU, Anderson AE, Isaacs JD
Publication type: Article
Publication status: Published
Journal: Arthritis and Rheumatology
Year: 2026
Pages: epub ahead of print
Online publication date: 01/07/2026
Acceptance date: 01/05/2026
Date deposited: 03/08/2026
ISSN (print): 2326-5191
ISSN (electronic): 2326-5205
Publisher: John Wiley and Sons Inc
URL: https://doi.org/10.1002/art.70235
DOI: 10.1002/art.70235
PubMed id: 42223208
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