Immunological dysregulation of follicular helper T cells, follicular regulatory T cells, and follicular cytotoxic T cells is associated with disease activity and identifies exploratory immune patterns in rheumatoid arthritis.

BACKGROUND: The onset and progression of rheumatoid arthritis (RA) are linked to autoantibody production driven by dysregulated germinal center (GC) responses. Follicular helper T cells (Tfh), follicular regulatory T cells (Tfr), and follicular cytotoxic T cells (Tfc) are important components of follicular immune regulation. However, the circulating profiles and clinical associations of these three cell subsets in the peripheral blood of RA patients remain underexplored through systematic investigations, and the specific function of Tfc cells in RA remains incompletely understood. METHODS: In the present study, peripheral blood samples were collected from 41 patients with RA and 16 healthy controls (HCs). Modified flow cytometry was employed to detect circulating Tfh, Tfr, and Tfc cells, with the aim of systematically investigating the clinical and immunological implications of these cell subsets in RA. RESULTS: (1) RA patients exhibited a disrupted Tfh/Tfr ratio in peripheral blood, accompanied by an elevated proportion of Tfc cells, both of which correlated with disease activity and autoantibody levels. (2) The ratio of Tfh/Tfr and the proportion of Tfc cells were significantly increased in patients with high disease activity of RA. (3) The frequency of Tfc cells showed a positive correlation with the frequency of Tfh cells and soluble interleukin-2 receptor (sIL-2R) levels. (4) Based on k-means unsupervised clustering analysis, patients with RA were grouped into three exploratory follicular T-cell-associated immune patterns: Cluster 3 patients displayed the highest disease activity, while Cluster 2 patients presented with the lowest white blood cell count. CONCLUSION: The dynamic imbalance of the circulating Tfh/Tfr/Tfc cells may reflect immune dysregulation in RA. The expansion of Tfc cells may be associated with systemic immune activation in RA. Exploratory clustering analysis further identified distinct follicular T-cell-associated immune patterns, providing new insights into RA immunological heterogeneity.