We have previously shown that expression of the Bcl‐3 gene, a member of the IκB family, is down‐regulated in CD4+ T cells from patients with rheumatoid arthritis (RA) following tocilizumab therapy. The objective of this study was to examine the role of Bcl‐3 in the pathogenesis of RA.

DNA microarray analysis was used to compare the signal intensity of Bcl‐3 in CD4+ T cells from untreated RA patients and healthy controls. We examined the roles of interleukin‐6 (IL‐6)/STAT‐3 signaling in the induction of Bcl‐3. In addition, we analyzed the gene expression profiles of Bcl‐3–transduced CD4+ T cells by RNA sequencing. The effects of enforced expression as well as gene silencing of Bcl‐3 on the development of follicular helper T (Tfh) cells were evaluated. Finally, we examined correlations between the signal intensities of Bcl‐3 and Tfh cell–related genes in CD4+ T cells from untreated RA patients.

Bcl‐3 levels were significantly higher in RA patients than in healthy controls. IL‐6 induced Bcl‐3 expression in CD4+ T cells in a STAT‐3–dependent manner. Transcriptome analysis revealed that the expression of Bcl‐6, a master regulator of Tfh cell differentiation, was significantly up‐regulated by the enforced Bcl‐3 expression. The enforced Bcl‐3 expression increased, but Bcl‐3 silencing decreased, the numbers of IL‐21–producing Tfh‐like cells. Bcl‐3 levels in CD4+ T cells from RA patients correlated positively with the levels of Tfh cell–related genes CXCR5, inducible costimulator, and achaete‐scute homolog 2.

Bcl‐3 is involved in the development of Tfh cells and the pathogenesis of RA, presumably by inducing IL‐21 production.