Reprogramming of Regulatory T cells to Promote Immune Tolerance

摘要 调节性T(Treg)细胞在增强外周免疫对自身抗原的耐受性方面发挥着基础性作用， 共生菌群和无害的外来抗原。转录因子Foxp3是Treg细胞不可缺少的 分化和免疫调节功能。Foxp3功能突变丧失导致严重的 自身免疫性炎症障碍，而慢性炎症性和自身免疫性获得性缺陷 疾病会破坏Treg细胞的稳定，并维持疾病的慢性化和严重性。Foxp3缺陷的Treg(∆Treg)细胞 缺乏抑制功能，表现为效应型T(Tef)细胞样表型。尽管如此，他们仍在继续 核心调控转录组，表明有可能恢复其调控功能。同意这一点 假说，我们最近证明了Foxp3缺乏会扰乱代谢检查点mTORC2 信号转导，促进有氧糖酵解和氧化磷酸化。具体删除 ∆Treg细胞中mTORC2接头基因Rictor显著改善Foxp3基因缺陷小鼠的疾病，改善∆Treg 抑制细胞的能力，并抑制他们的Tef细胞样的糖酵解和呼吸程序。这些 首次证实了对∆树突状细胞进行重新编程以有利于增强耐受性的可能性 方法既适用于单基因免疫失调疾病，也适用于常见的免疫调节失调疾病。最近，我们已经 证实了∆树突状细胞是异质性的，从高调控的细胞到 向更高级的Tef细胞样表型发展的潜能。 根据这些结果，我们推测FOXP3缺陷会破坏∆树突状细胞的稳定性，使其趋向于类似于Tef细胞的程序 这是一个循序渐进的过程，可以通过精确干预来逆转，以重新建立它们的监管职能。 具体地说，CD25Treg细胞向∆样细胞的退化涉及从CD25Foxp1高表达细胞的转变 分化为CD25-Foxp1low激活的Teff样细胞，最终形成缺乏Treg细胞的ex-Treg细胞 表观遗传印记。IL-2/CD25和Foxp1在这一转变中的作用将通过功能和 遗传方法(目标1)。在目标2下，我们将检查这一过渡过程中涉及的代谢检查点 以及有针对性的组合代谢和功能干预重新编程∆Treg细胞的能力 宽容的一面。在目标3下，我们将利用从初步研究和拟议研究中获得的见解来加强 自身免疫和炎症性疾病背景下Foxp3充足的Treg细胞的调节功能 模特们。∆树突状细胞亚群的分析及其单一和组合的调制 介入策略代表了一种恢复单基因和普通型免疫耐受的新方法 免疫调节失调疾病，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.