IL-2R-dependent mechanisms in regulation of Treg homeostasis and autoimmunity

最初在我的实验室开创的研究以及我们和其他人随后的工作确定了IL-2是一种必需的免疫调节剂。 调节性T细胞（Tcells）的发育、稳态和功能的细胞因子。我们进一步 在小鼠模型中建立了低水平的IL-2R信号传导有效地促进Treg而不是T效应子（Teff） 细胞这些发现有助于低剂量IL-2作为Treg靶向治疗的临床转化， 自身免疫此外，严重的自身免疫相关的副作用经常发生的后果， 癌症免疫治疗期间的检查点阻断，提高了低剂量IL-2可能减轻 这些不必要的回应。尽管取得了这一进展，我们仍然对这些机制缺乏了解， 其中IL-2控制外周T淋巴细胞。最近，我们开发了几种新的小鼠模型， 2R信号转导在TdR中。在一个模型（NOD-Y3）中，IL-2R信号强度在24小时内降低了约3倍。 NOD小鼠中的睾酮，这加速了糖尿病。在另一个模型中，CD25（IL-2R α）在小鼠中被选择性消除。 外周T细胞（CD25iKO小鼠），其中所有外周T细胞需要IL-2R信号传导以使其存活。我们 全基因组表达研究表明，在缺乏IL-2R信号转导的情况下，TGFAP的稳态受损 由于胆固醇生物合成减少，改变了Treg代谢， 凋亡Bcl-2，其有利于凋亡。虽然Treg抑制功能依赖于IL-2R信号传导， 这一概念的明确数据来自于IL-2R信号传导在胸腺发育过程中受损的研究。 对IL-2无反应的外周TGFAP的抑制活性仍然未知。此外，委员会认为， 目前的模型表明，IL-2R信号转导主要是静息或中枢T细胞稳态所必需的。 TCR信号传导控制活化的或效应Treg（eTclG）。然而，我们发现eTreg 没有IL-2亚群不能存活。因此，IL-2对eTlymphoma的作用仍不清楚。我们的研究还表明 减少，但不是不存在，IL-2R信号转导在T细胞水平足以促进自身免疫- NOD小鼠的糖尿病。然而，IL-2依赖性过程在胰岛内受损， 胰腺加速糖尿病是知之甚少。我们计划在这些成果的基础上再接再厉， IL-2R的专业知识，以解决这些问题，并更好地了解机制的基础上，IL-2R 信号传导调节Treg稳态并促进对自身免疫的易感性。以下目标是 提出：1）建立依赖于IL-2R、STAT5和IL-10的外周Treg亚群的基因标签。 2）为了确定IL-2R、STAT5和mTORC 1信号传导对于存活和存活的相对作用， 代谢功能，包括脂质生物合成和Bcl-2的贡献，为外周血的稳态 3）为了确定IL-2R、STAT5和mTORC 1信号传导缺失改变Treg功能的程度， 确定减少，而不是缺失，IL-2R信号转导在T细胞中促进的细胞和分子基础 NOD小鼠的自身免疫。

Studies initially pioneered in my lab and subsequent work by us and others established that IL-2 is an essential cytokine for the development, homeostasis and function of regulatory T cells (Tregs). We have further established in mouse models that low levels of IL-2R signaling effectively promote Treg but not T effector (Teff) cells. These findings have helped in the clinical translation of low-dose IL-2 as a Treg-targeted therapy for autoimmunity. Moreover, serious autoimmune-related side effects frequently occur as a consequence of checkpoint blockade during cancer immunotherapy, raising the possibility that low-dose IL-2 might alleviate these unwanted responses. In spite of this progress, we still have a poor understanding of the mechanisms by which IL-2 controls peripheral Tregs. Recently, we have developed several novel mouse models that vary IL- 2R signaling in Tregs. In one model (NOD-Y3), IL-2R signaling strength was lowered approximately 3-fold in Tregs in NOD mice, which accelerated diabetes. In another model, CD25 (IL-2Rα) was selectively abrogated in peripheral Tregs (CD25iKO mice), where all peripheral Tregs require IL-2R signaling for their survival. Our genome-wide expression studies suggests homeostasis of Tregs is impaired in the absence of IL-2R signaling due to decreased cholesterol biosynthesis that alters Treg metabolism and to lower expression of anti- apoptotic Bcl-2 that favors apoptosis. Although Treg suppressive function depends on IL-2R signaling, definitive data for this notion comes from studies where IL-2R signaling is impaired during thymic development. The suppressive activity of peripheral Tregs that have not responded to IL-2 remains unknown. Moreover, current models suggest that IL-2R signaling is primarily required for the homeostasis of resting or central Tregs (cTregs) while TCR signaling controls activated or effector Treg (eTregs). However, we found that the eTreg subset cannot survive without IL-2. Thus, the role of IL-2 for eTregs remains unclear. Our studies also indicate that reduced, but not absent, IL-2R signaling at the level of Tregs is sufficient to promote autoimmune- mediated diabetes in NOD mice. However, IL-2-dependent processes that are impaired within the islets of the pancreas to accelerate diabetes are poorly understood. We plan to build on these results and capitalize on our expertise on the IL-2R to address these issues and better understand mechanistically the basis by which IL-2R signaling regulates Treg homeostasis and promotes susceptibility to autoimmunity. The following aims are proposed: 1) To establish the gene signatures for peripheral Treg subsets that depend on IL-2R, STAT5 and mTORC1 signaling; 2) To determine the relative roles of IL-2R, STAT5 and mTORC1 signaling for survival and metabolic function, including the contribution of lipid biosynthesis and Bcl-2, for the homeostasis of peripheral Treg subsets; 3) To define the extent absent IL-2R, STAT5, and mTORC1 signaling alters Treg function and to determine the cellular and molecular basis by which reduced, not absent, IL-2R signaling in Tregs promotes autoimmunity in NOD mice.