Homeostatic signals induce the development of peripheral helper T cells promoted in the pathogenesis of rheumatoid arthritis

Dysregulated T cell homeostasis has been implicated in the pathogenesis of rheumatoid arthritis (RA), in the joint of which peripheral helper T (Tph) cells accumulate and form ectopic lymphoid organs. We examined whether homeostatic signals are involved in the development of Tph cells. Human peripheral blood mononuclear cells(PBMCs) were cultured with IL-7, resulting in the development of PD-1highCXCR5+ Tph-like cells from human peripheral blood CD4 T cells after culture. These IL-7-induced Tph-like (IL-7-Tph) cells produced CXCL13 and IL-21 and helped B cells produce IgG. Comprehensive gene expression analysis further supported their similarity with Tph cells in RA joint, and synovial fluid from RA patients (RASF) greatly promoted the IL-7-induced development of Tph-like cells. Our results demonstrate an antigen-nonspecific developmental pathway of Tph cells triggered by homeostatic signals and promoted by the local joint environment, which accounts for the accumulation of Tph cells in RA joints. Overall design: Development of Tph-like cells was assessed by flow cytometry, gene expression, and functional analysis. To further verify the similarity between IL-7-Tph and RA-Tph cells, transcriptome analysis by bulk RNAseq was performed.