IL-12 drives the differentiation of human T follicular regulatory cells

IF 17.6 1区医学 Q1 IMMUNOLOGY

Science Immunology Pub Date : 2024-07-05 DOI:10.1126/sciimmunol.adf2047

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

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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.

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IL-12 驱动人类 T 滤泡调节细胞的分化。

T滤泡调节（Tfr）细胞可以抵消T滤泡辅助（Tfh）细胞的B细胞辅助活性，阻碍产生针对自身抗原或过敏原的抗体。目前还缺乏对启动人类调节性 T（Treg）细胞向 Tfr 细胞分化的细胞因子的机理认识。在这里，我们报告了低剂量的促Tfh细胞因子白细胞介素-12（IL-12）能在活化的人类Treg细胞上诱导Tfr细胞程序，同时还能保留它们的调节功能。从机理上讲，我们发现IL-12会导致STAT4（信号转导和转录激活因子4）磷酸化并与IL-12驱动的滤泡特征基因结合。IL12RB1基因存在先天性免疫错误的患者体内循环Tfr细胞显著减少，并产生更高水平的抗肌动蛋白自身抗体。总之，这项研究揭示了IL-12是体内Tfr细胞分化的诱导剂，并为体外生成人类Tfr样细胞提供了一种方法。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Science Immunology Immunology and Microbiology-Immunology

CiteScore

32.90

自引率

2.00%

发文量

183

期刊介绍： Science Immunology is a peer-reviewed journal that publishes original research articles in the field of immunology. The journal encourages the submission of research findings from all areas of immunology, including studies on innate and adaptive immunity, immune cell development and differentiation, immunogenomics, systems immunology, structural immunology, antigen presentation, immunometabolism, and mucosal immunology. Additionally, the journal covers research on immune contributions to health and disease, such as host defense, inflammation, cancer immunology, autoimmunity, allergy, transplantation, and immunodeficiency. Science Immunology maintains the same high-quality standard as other journals in the Science family and aims to facilitate understanding of the immune system by showcasing innovative advances in immunology research from all organisms and model systems, including humans.