Reprogramming of Regulatory T cells to Promote Immune Tolerance

摘要 调节性T（Treg）细胞在增强对自身抗原的外周免疫耐受性中起着重要作用， 寄生植物群和无害的外来抗原。转录因子Foxp 3对Treg细胞是不可缺少的 分化和免疫调节功能。Foxp 3的功能缺失突变会导致严重的 自身免疫性炎症性疾病，而获得性缺乏慢性炎症和自身免疫性 这些条件使Treg细胞不稳定并维持疾病的慢性和严重性。Foxp 3-缺陷型Treg（Treg）细胞 缺乏抑制功能并表现出效应T（Teff）细胞样表型。然而，他们继续 核心调控转录组，表明有潜力恢复其调控功能。同意这一 假设，我们最近证明Foxp 3缺陷失调代谢检查点mTORC 2 信号传导并引起有氧糖酵解和氧化磷酸化增强。具体删除 在Foxp 3缺陷小鼠中，mTORC 2衔接基因Rictor显著改善了Foxp 3缺陷小鼠的疾病， 细胞抑制能力，并抑制其Teff细胞样糖酵解和呼吸程序。这些 这些发现首次确立了重新编程CD 3 Treg细胞以增强耐受性的潜力， 方法适用于单基因和常见的免疫失调疾病。最近，我们有 已经确定，CD 3 Treg细胞是异质性的，沿着一个谱，从具有高调节性的细胞到具有高调节性的细胞， 可能是更先进的Teff细胞样表型。 基于这些结果，我们假设Foxp 3缺陷使Treg细胞向Teff细胞样程序不稳定 这是一个循序渐进的过程，可以通过精确干预来逆转，以重新建立其监管职能。 具体地说，CD 25 + Treg细胞变性为Tef样细胞涉及从CD 25 + Foxp 1high细胞向Tef样细胞的转变。 CD 25-Foxp 1 low活化的Tef样细胞，最终以缺乏Treg细胞的ex-Treg细胞形式出现 表观遗传印记IL-2/CD 25和Foxp 1在这一转变中的作用将通过功能和 遗传学方法（目标1）。在目标2中，我们将研究参与这一转变的代谢检查点 以及靶向组合代谢和功能干预重新编程CD 3 Treg细胞的能力， 宽容。在目的3下，我们会运用初步研究和拟议研究所得的见解， Foxp 3-充足Treg细胞在自身免疫性和炎症性疾病背景下的调节功能 模型所提出的对CD 34 + Treg细胞亚群及其通过单一和组合免疫调节的调节的分析， 干预策略代表了一种新的方法，以恢复免疫耐受性，在单基因和常见的 免疫失调性疾病，包括自身免疫性和过敏性疾病以及移植物抗宿主病。

ABSTRACT Regulatory T (Treg) cells play a fundamental role in enforcing peripheral immunological tolerance to self-antigens, commensal flora, and innocuous foreign antigens. The transcription factor Foxp3 is indispensable to Treg cell differentiation and immunoregulatory functions. Loss of function mutations in Foxp3 precipitate a severe autoimmune inflammatory disorder, while acquired deficiency in chronic inflammatory and autoimmune conditions destabilizes Treg cells and sustains disease chronicity and severity. Foxp3-deficient Treg (∆Treg) cells lack suppressor function and manifest an effector T (Teff) cell–like phenotype. Nevertheless, they continue to a core regulatory transcriptome, indicating the potential to restore their regulatory function. In agreement with this hypothesis, we have recently demonstrated that Foxp3 deficiency dysregulates metabolic checkpoint mTORC2 signaling and gives rise to augmented aerobic glycolysis and oxidative phosphorylation. Specific deletion of the mTORC2 adaptor gene Rictor in ∆Treg cells greatly ameliorated disease in Foxp3-deficient mice, improved ∆Treg cells suppressive capacities, and suppressed their Teff cell–like glycolytic and respiratory programs. These findings established for the first time the potential to reprogram ∆Treg cells in favor of enhanced tolerance, an approach applicable to both monogenic and common immune dysregulatory diseases. More recently, we have established that the ∆Treg cells are heterogenous, ranging along a spectrum from cells with high regulatory potential to ones more advanced towards a Teff cell-like phenotype. Based on these results, we postulate that Foxp3 deficiency destabilizes ∆Treg cells towards Teff cell-like programs in a step-wise process that can be reversed by precision interventions to re-establish their regulatory functions. Specifically, the degeneration of ∆Treg cells in to Teff-like cells involves the transition from a CD25+Foxp1high cell population into CD25–Foxp1low activated Teff-like cells that ultimately emerge as ex-Treg cells lacking in a Treg cell epigenetic imprint. The role of IL-2/CD25 and Foxp1 in this transition will be examined using functional and genetic approaches (Aim 1). Under Aim 2, we will examine the metabolic checkpoints involved in this transition and the capacity of targeted combinatorial metabolic and functional interventions to reprogram ∆Treg cells in favor of tolerance. Under Aim 3, we will employ insights gained from our preliminary and proposed studies to reinforce the regulatory functions of Foxp3-sufficient Treg cells in the context of autoimmune and inflammatory disease models. The proposed analysis of ∆Treg cell subsets and their modulation by single and combinatorial interventional strategies represents a novel approach to restoring immune tolerance in monogenic and common immune dysregulatory diseases, including autoimmune and allergic disorders and graft versus host disease.