Abstract：
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.
摘要：
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，并阻碍针对自身抗原或过敏原的抗体的产生。对启动人调节性T（Treg）细胞分化为Tfr细胞的细胞因子的机制理解仍然缺失。在这里，我们报道,低剂量的pro-Tfh细胞因子白介素-12(IL-12)在激活的人Treg细胞上驱动Tfr细胞程序的诱导,同时也保持其调节功能.机械上,我们发现IL-12导致STAT4(信号转导和转录激活因子4)磷酸化,并与IL-12驱动的卵泡标记基因结合.IL12RB1基因中先天性免疫错误的患者在循环Tfr细胞中表现出强烈的减少，并在体内产生更高水平的抗肌动蛋白自身抗体。总的来说,这项研究揭示了IL-12作为体内Tfr细胞分化的诱导剂，并为体外产生人Tfr样细胞提供了一种方法。
