Instructor Brigham and Women’s Hosp, Harvard Med. Sch., United States
Disclosure(s):
Byunghee Koh, PH.d: No financial relationships to disclose
Introduction/Rationale: Regulatory T cells (Tregs) are enriched in the synovial tissue of patients with rheumatoid arthritis (RA), yet fail to restrain chronic inflammation. Peripheral helper T (Tph) cells, defined by CXCL13 and IL-21 expression, promote local B cell activation and autoantibody production in RA, but their developmental origin in human tissue remains unclear. We investigated whether human Tregs can acquire Tph-like features within the inflammatory synovial microenvironment.
Methods: RA synovial tissues were analyzed using integrated single-cell RNA sequencing and T cell receptor (TCR) repertoire profiling. Cellular neighborhood analysis (CNA) was used to define tissue-level associations between T cell subsets and myeloid populations. Functional assays were performed using in vitro–stimulated human Tregs to assess proliferation, suppressive capacity, epigenetic stability, cytokine production, and plasmablast differentiation.
Results: Single-cell transcriptomic and TCR analyses revealed marked transcriptional convergence and clonal overlap between Tregs and Tph cells, suggesting a shared developmental relationship. CNA identified Tph-enriched neighborhoods closely associated with inflammatory macrophages. Both synovial Tregs and Tph cells exhibited elevated glycolytic gene signatures. Experimentally, TNFR2 stimulation of human Tregs, particularly in the presence of IL-6, induced a proliferative but unstable state characterized by reduced FOXP3 expression, diminished suppressive function, increased TSDR methylation, and induction of CXCL13 and IL-21. These reprogrammed Tregs promoted plasmablast differentiation in vitro.
Conclusion: These findings indicate that inflammatory and metabolic cues in RA synovium can actively reprogram human Tregs toward a Tph-like effector state. This work provides insight into how regulatory dysfunction contributes to sustained B cell–mediated pathology in autoimmune arthritis and highlights the importance of tissue context in shaping Treg fate.
