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.