IL-6-induced C/EBPα drives follicular regulatory T cell differentiation to regulate humoral immunity in mice

Follicular regulatory T (Tfr) cells maintain immune homeostasis by suppressing excessive germinal center (GC) responses. However, the molecular mechanisms governing Tfr differentiation remain incompletely understood. Here, we identify interleukin-6 (IL-6) as a key regulator of Tfr generation. IL-6/IL-6Rα signaling promotes the differentiation of regulatory T cells (Treg) into Tfr cells by inducing CCAAT/enhancer binding protein α (C/EBPα), which binds the Bcl6 and Cxcr5 promoters in Tfr cells. Treg-specific deletion of C/EBPα in mice impairs Tfr differentiation, resulting in hyperactive GC responses and exacerbated pathology in mouse models of systemic lupus erythematosus (SLE) and HDM-induced allergy. In humans, in silico perturbation of CEBPA in Tregs disrupts the Tfr differentiation trajectory. Furthermore, CEBPA expression in Tregs, but not total CD4+ T cells, from patients with SLE negatively correlates with disease activity (SLEDAI). Thus, these findings establish the IL-6–C/EBPα axis as a critical mechanism driving Tfr differentiation to restrain pathogenic humoral immunity. Follicular regulatory T cells (Tfr) contribute to the maintenance of humoral immune homeostasis by modulating aberrant germinal center (GC) activation. Cytokine signaling contributes to Tfr differentiation; however, the complete cytokine landscape regulating Tfr biology has yet to be determined. Here, the authors identify an IL-6-C/EBPα axis that drives Tfr cell differentiation via upregulation of Bcl6 and CXCR5 protein and show that the dysregulation of this axis alters Tfr-mediated suppression of B cell responses, exacerbating SLE pathology and allergic responses in mice.