Schuster Marc, Plaza-Sirvent Carlos, Matthies Anne-Marie, Heise Ulrike, Jeron Andreas, Bruder Dunja, Visekruna Alexander, Huehn Jochen, Schmitz Ingo
Systems-Oriented Immunology and Inflammation Research Group, Helmholtz Centre for Infection Research, 38124 Braunschweig, Germany.
Institute of Molecular and Clinical Immunology, Otto-von-Guericke University, 39120 Magdeburg, Germany.
J Immunol. 2017 Aug 1;199(3):920-930. doi: 10.4049/jimmunol.1600877. Epub 2017 Jun 26.
Foxp3-expressing regulatory T cells (Tregs) are essential regulators of immune homeostasis and, thus, are prime targets for therapeutic interventions of diseases such as cancer and autoimmunity. c-REL and IκB are important regulators of Foxp3 induction in Treg precursors upon γ-chain cytokine stimulation. In c-REL/IκB double-deficient mice, Treg numbers were dramatically reduced, indicating that together, c-REL and IκB are pivotal for Treg development. However, despite the highly reduced Treg compartment, double-deficient mice did not develop autoimmunity even when aged to more than 1 y, suggesting that c-REL and IκB are required for T cell effector function as well. Analyzing Treg development in more detail, we identified a CD122 subset within the CD25Foxp3 precursor population, which gave rise to classical CD25Foxp3 Treg precursors. Importantly, c-REL, but not IκB, controlled the generation of classical CD25Foxp3 precursors via direct binding to the locus. Thus, we propose that CD4GITRCD122CD25Foxp3 cells represent a Treg pre-precursor population, whose transition into Treg precursors is mediated via c-REL.
表达叉头框蛋白3（Foxp3）的调节性T细胞（Tregs）是免疫稳态的重要调节因子，因此是癌症和自身免疫性疾病等疾病治疗干预的主要靶点。c-REL和IκB是γ链细胞因子刺激后Treg前体细胞中Foxp3诱导的重要调节因子。在c-REL/IκB双缺陷小鼠中，Treg数量显著减少，表明c-REL和IκB共同对Treg发育至关重要。然而，尽管Treg区室高度减少，但双缺陷小鼠即使年龄超过1岁也未发生自身免疫，这表明c-REL和IκB对T细胞效应功能也是必需的。更详细地分析Treg发育过程中，我们在CD25Foxp3前体细胞群体中鉴定出一个CD122亚群，它产生了经典的CD25Foxp3 Treg前体细胞。重要的是，c-REL而非IκB通过直接结合 位点来控制经典CD25Foxp3前体细胞的产生。因此，我们提出CD4GITRCD122CD25Foxp3细胞代表一种Treg前前体细胞群体，其向Treg前体细胞的转变是通过c-REL介导的。
