Osamu Iri

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.

Human CD4 ⁺ T cells play a central role in the pathogenesis of autoimmune diseases, but their immunoregulatory mechanisms driving pathogenesis remain to be elucidated. We show that human T peripheral helper cells (T _PH cells) regulate peripheral immune responses via insulin-like growth factor–like family member 2 (IGFL2), an inflammatory factor found exclusively in primates. Single-cell RNA sequencing of seropositive rheumatoid arthritis (RA) synovium showed that IGFL2 is specifically expressed by CD4 ⁺ T cells, predominantly T _PH cells. IGFL2 promotes transforming growth factor–β–induced CXCL13 production in CD4 ⁺ T cells, activates nuclear factor κB signaling, and induces monocyte gene signatures like those of pathogenic macrophages. CRISPR-Cas9 knockout of IGFL2 in synovial T _PH cells suppressed this gene signature in cocultured monocytes. Blood IGFL2 protein levels correlated with RA disease severity and could be used as a potential biomarker. These findings highlight the involvement of IGFL2 in RA pathogenesis, emphasizing how human T _PH cells regulate local immune responses via IGFL2.