%0 Journal Article
%T IL-12 drives the differentiation of human T follicular regulatory cells.
%A Castaño D
%A Wang S
%A Atencio-Garcia S
%A Shields EJ
%A Rico MC
%A Sharpe H
%A Bustamante J
%A Feng A
%A Le Coz C
%A Romberg N
%A Tobias JW
%A Utz PJ
%A Henrickson SE
%A Casanova JL
%A Bonasio R
%A Locci M
%J Sci Immunol
%V 9
%N 97
%D 2024 Jul 5
%M 38968337
%F 30.63
%R 10.1126/sciimmunol.adf2047
%X T follicular regulatory (Tfr) cells can counteract the B cell helper activity of T follicular helper (Tfh) 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 (Treg) cells into Tfr cells is still missing. Herein, we report that low doses of the pro-Tfh cytokine interleukin-12 (IL-12) drive the induction of a Tfr cell program on activated human Treg 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 Tfr cells and produced higher levels of anti-actin autoantibodies in vivo. Overall, this study unveils IL-12 as an inducer of Tfr cell differentiation in vivo and provides an approach for the in vitro generation of human Tfr-like cells.