IL-12 drives the differentiation of human T follicular regulatory cells

T follicular regulatory (T_fr) cells can counteract the B cell helper activity of T follicular helper (T_fh) cells and hinder the production of antibodies against self-antigens or allergens. A mechanistic understanding of the cytokines initiating the differentiation of human regulatory T (T_reg) cells into T_fr cells is still missing. Herein, we report that low doses of the pro-T_fh cytokine interleukin-12 (IL-12) drive the induction of a T_fr cell program on activated human T_reg cells while also preserving their regulatory function. Mechanistically, we found that IL-12 led to STAT4 (signal transducer and activator of transcription 4) phosphorylation and binding to IL-12–driven follicular signature genes. Patients with inborn errors of immunity in the IL12RB1 gene presented with a strong decrease in circulating T_fr cells and produced higher levels of anti-actin autoantibodies in vivo. Overall, this study unveils IL-12 as an inducer of T_fr cell differentiation in vivo and provides an approach for the in vitro generation of human T_fr-like cells.