Yuki Masuo, MD: No financial relationships to disclose
Introduction/Rationale: Peripheral helper T (Tph) cells can contribute to the pathogenesis of human autoimmune diseases. Although Tph cells are recognized as the major B-cell helpers in inflamed joints of rheumatoid arthritis (RA), the mechanisms underlying their maintenance, activation, and involvement in tissue inflammation remain poorly understood.
Methods: We applied multiple sequencing technologies, including scRNA-seq, CITE-seq, scTCR-seq, scBCR-seq and scATAC-seq, on cells from synovial tissue (ST), synovial fluid and peripheral blood from RA patients. ST sections were utilized for spatial transcriptomics data acquisition. In vitro validation experiments, such as T cell-B cell coculture and gene editing, were also performed.
Results: We recently demonstrated that Tph cells comprise two distinct subsets in RA: stem-like Tph (S-Tph) and effector Tph (E-Tph) cells (Masuo et al., Sci Immunol., 2025). S-Tph cells showed self-renewal capacity and were mainly found within tertiary lymphoid structures (TLSs) together with B cells. By contrast, E-Tph cells expressed various effector molecules capable of activating macrophages. Most E-Tph cells were located outside TLSs and interacted with proinflammatory macrophages. S-Tph cells were able to differentiate into E-Tph cells when cocultured with B cells, while concurrently inducing potent immunoglobulin production by B cells. Extending our T cell analysis, scRNA-seq of B cells revealed the presence of naive, memory, GC-like, ABCs, and ASCs. Among these B cell subsets, the frequency of S-Tph cells in ST correlated most strongly with that of GC-like B cells.
Conclusion: These findings indicate that interactions between S-Tph and B cells within TLSs of RA synovium are crucial for sustaining Tph population by promoting S-Tph self-renewal and differentiation into E-Tph cells. Our study offers a rationale to target S-Tph cells for the treatment of RA characterized by persistent tissue inflammation with an expectation to reduce global Tph responses and TLS formation.
