Stem-like and effector peripheral helper T cells comprise distinct subsets in rheumatoid arthritis

Peripheral helper T (TPH) cells can play pathogenic roles in human autoimmune diseases. TPH cells are proposed to be the major B cell helpers in inflamed joints in rheumatoid arthritis (RA), but whether and how TPH cells are engaged in tissue inflammation remains unclear. We demonstrate that TPH cells comprise two subsets in RA: stem-like TPH (S-TPH) and effector TPH (E-TPH) cells. These two subsets differed in transcriptome, epigenome, B cell helper capacity, spatial localization, and cell interactions. S-TPH cells displayed self-renewal capacity and were mainly found within tertiary lymphoid structures (TLSs) in synovial tissue together with B cells. S-TPH cells potently induced B cells to produce immunoglobulins. By contrast, E-TPH cells expressed effector molecules and colocalized with proinflammatory macrophages and CD8+ T cells outside TLSs. S-TPH cells could differentiate into E-TPH cells upon TCR stimulation and coculture with B cells. Collectively, our study shows that S-TPH cells play a central role in promoting TPH responses by undergoing self-renewal and seeding E-TPH cells.