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. 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.