IL-12 drives the differentiation of human T follicular regulatory cells
Diana Castaño, Sidney Wang, Segovia Atencio-Garcia, Emily J. Shields, Maria C. Rico, Hannah Sharpe, Jacinta Bustamante, Allan Feng, Carole Le Coz, Neil Romberg, John W. Tobias, Paul J. Utz, Sarah E. Henrickson, Jean‐Laurent Casanova, Roberto Bonasio, Michela Locci
Abstract
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.