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

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