BACKGROUND: CD4 T cells specific for citrullinated (cit)-peptides are key players in RA immunopathogenesis. Characterising 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. METHODS: Cit-peptide specific (autoreactive) CD4 T cells from HLA-DRB1 04:01 positive HCs (n=9), RA patients at different disease stages (n= 17 pre-treatment, 13 on treatment) and 6 at-risk individuals were assessed using MHC II-peptide tetramers combined with spectral flow cytometry. Autoreactive T cell frequency and phenotype was 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 naïve. In early pre-treatment RA, autoreactive memory T cells demonstrated downregulation 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 prior to RA onset. CONCLUSION: In RA, CD4 T-cell autoreactivity is characterised by a surface phenotype that suggests in vivo activation and the potential to acquire cytotoxic capacity, whereas healthy autoreactivity demonstrates naïvety. These observations suggest maturing autoreactivity in RA and may provide novel tools for monitoring disease progression and tolerance.
Stanway et al. (Mon,) studied this question.