Stem-like and effector peripheral helper T cells orchestrate distinct local immune responses in rheumatoid arthritis 2262732

Abstract

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. 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. 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. 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. Japan Agency for Medical Research and Development grant Immune Mechanisms of Human Disease (HUM)