| Autor: |
Castaño, Diana, Wang, Sidney, Atencio-Garcia, Segovia, Shields, Emily J., Rico, Maria C., Sharpe, Hannah, Bustamante, Jacinta, Feng, Allan, Le Coz, Carole, Romberg, Neil, Tobias, John W., Utz, Paul J., Henrickson, Sarah E., Casanova, Jean-Laurent, Bonasio, Roberto, Locci, Michela |
| Předmět: |
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| Zdroj: |
Science Immunology; Jul2024, Vol. 9 Issue 97, p1-17, 17p |
| Abstrakt: |
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. Editor's summary: T follicular regulatory (Tfr) cells balance the activity of T follicular helper cells and suppress B cell responses to self-antigens and allergens. However, the key signals involved in Tfr cell differentiation, particularly in humans, remain incompletely understood. By screening the effects of multiple cytokines on human regulatory T cells, Castaño et al. identified interleukin-12 (IL-12) as the most potent inducer of Tfr cell differentiation in vitro. IL-12 promoted the acquisition of a follicular gene expression program and STAT4 (signal transducer and activator of transcription 4) binding at signature follicular loci. In addition, patients bearing mutations in the IL12RB1 gene displayed a strong decrease in circulating Tfr cells. Together, these findings identify IL-12 as a driver of human Tfr cell differentiation, thus enabling their in vitro generation. —Claire Olingy [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
| Externí odkaz: |
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