1. IL-12 drives the differentiation of human T follicular regulatory cells.
- Author
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Castaño D, Wang S, Atencio-Garcia S, Shields EJ, Rico MC, Sharpe H, Bustamante J, Feng A, Le Coz C, Romberg N, Tobias JW, Utz PJ, Henrickson SE, Casanova JL, Bonasio R, and Locci M
- Subjects
- Humans, STAT4 Transcription Factor immunology, STAT4 Transcription Factor genetics, Receptors, Interleukin-12 immunology, Receptors, Interleukin-12 genetics, Female, Male, Interleukin-12 immunology, Cell Differentiation immunology, T-Lymphocytes, Regulatory immunology
- Abstract
T follicular regulatory (T
fr ) 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.- Published
- 2024
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