PGI2 augments Treg function

一个功能最佳的免疫系统需要在保护性反应之间取得平衡， 环境病原体和对无害环境抗原的耐受性应答。破裂 对无害的环境抗原的耐受性导致抗原成为过敏原， 炎症和疾病。调节性T细胞（Treg）是发展和维持免疫系统的核心。 对过敏原的耐受性;然而，Treg不能支持过敏原患者耐受性的机制， 过敏性疾病没有完全定义。在这个应用中，我们的初步数据强烈支持宿主的 不能通过前列腺素（PG）I2受体发出信号阻碍免疫耐受， PGI2类似物促进耐受性。具体来说，我们发现胸腺Treg（tTreg）中PGI2信号缺陷 导致Foxp3表达降低，抑制功能降低，抑制IL-10产生， 下调诱导型Treg（iTreg）分化。我们还发现，来自PGI2缺陷小鼠的Treg 受体IP（IP KO）小鼠在体内过继转移模型中没有抑制2型细胞因子的产生。 与来自WT小鼠的Treg相比的过敏性炎症。因此，我们的总体假设是，PGI2 促进Treg的免疫抑制功能。为了验证这一假设，我们有两个具体目标。 具体目标1是确定内源性PGI2信号传导促进Treg功能的能力。在这 我们假设：a）具有缺陷的PGI2信号传导的抗原特异性Treg具有抑制性抑制， 与抗原特异性WT Treg相比，哮喘的主要特征，B）PGI2信号传导促进Treg 在过敏原激发的情况下的稳定性，以及c）PGI2信号传导抑制Treg上的ST2表达，并且 PGI2信号传导缺陷破坏Treg功能，促进致病性IL-13表达的发展， ST2 + Treg.具体目标2是确定外源性PGI2信号传导促进Treg表达的能力。 功能在这个目标中，我们假设：a）Treg的PGI2类似物离体处理增强了Treg表达的能力。 iTreg抑制过敏性炎症，B）外源性给予PGI2类似物增加Treg功能， 抑制过敏性炎症，和c）PGI2类似物通过以下方式增强IL-10产生和抑制功能： 人iTreg对IL-2和TGF-β活化的响应。这些研究是范式转变，因为 目前还没有已知的促进Treg功能的药物，我们的初步数据显示， 强烈支持PGI2可能是第一个被描述的。使用人类细胞和小鼠的拟议实验 将推进该领域，因为他们将进一步定义调节Treg功能的机制。的 目前PGI2用于人类治疗的可用性突出了我们研究的临床意义， 该疗法可以立即重新用于治疗过敏性呼吸道疾病如哮喘。

An optimally functioning immune system requires a balance between protective responses against environmental pathogens and tolerogenic responses to innocuous environmental antigens. The breakdown of tolerance to harmless environmental antigens results in antigens becoming allergens that induce allergic inflammation and disease. Regulatory T cells (Treg) are central to the development and maintenance of tolerance to allergens; however, the mechanisms by which Treg fail to support tolerance in patients with allergic disease are not fully defined. In this application, our preliminary data strongly support that a host's inability to signal through the prostaglandin (PG)I2 receptor impedes immune tolerance and that treatment with PGI2 analogs promotes tolerance. Specifically, we found that defective PGI2 signaling in thymic Treg (tTreg) resulted in decreased Foxp3 expression, reduced suppressive function, inhibited IL-10 production, and downregulated inducible Treg (iTreg) differentiation. We also showed that Treg from mice deficient in the PGI2 receptor IP (IP KO) mice did not suppress type 2 cytokine production in an in vivo adoptive transfer model of allergic inflammation compared to Treg from WT mice. Therefore, our overarching hypothesis is that PGI2 promotes the immunosuppressive functions of Treg. To test this hypothesis, we have two specific aims. Specific Aim 1 is to determine the ability of endogenous PGI2 signaling to promote Treg function. In this aim we hypothesize that: a) antigen-specific Treg that have deficient PGI2 signaling have inhibited suppression of the cardinal features of asthma compared to antigen-specific WT Treg, b) PGI2 signaling promotes Treg stability in the setting of allergen challenge, and c) PGI2 signaling restrains ST2 expression on Treg, and that a deficiency of PGI2 signaling corrupts Treg function promoting the development of pathogenic IL-13 expressing ST2+ Treg. Specific Aim 2 is to determine the ability of exogenous PGI2 signaling to promote Treg function. In this aim we hypothesize that: a) PGI2 analog treatment of Treg ex vivo enhances the ability of iTreg to restrain allergic inflammation, b) exogenous administration of a PGI2 analog increases Treg function to suppress allergic inflammation, and c) PGI2 analogs enhance IL-10 production and suppressive function by human iTreg in response to activation with IL-2 and TGF-β. These studies are paradigm shifting because there are currently no known pharmacologic agents which promote Treg function and our preliminary data strongly supports that PGI2 may be the first described. The proposed experiments using human cells and mice will advance the field in that they will further define the mechanisms by which Treg function is regulated. The current availability of PGI2 for human treatment highlights the clinical significance of our studies as this therapy could be immediately repurposed for the treatment of allergic respiratory diseases such as asthma.