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.