SHP 1 Regulates Conventional T cell Resistance to Regulatory T Cell Suppression

描述（由申请人提供）：本提案的目标是了解控制常规T细胞（Tcon）对调节性T细胞（Treg）介导的抑制的分子机制，并确定用于免疫治疗的潜在分子靶点。过去十年的研究表明，Treg细胞是健康免疫系统的重要组成部分。一旦通过它们的T细胞受体（TCR）激活，Treg细胞可以抑制广泛的免疫细胞。越来越明显的是，在许多自身免疫性疾病中，Treg细胞保持功能，但不能控制Tcon细胞。同时，Treg细胞通过形成抑制性肿瘤微环境阻碍抗肿瘤免疫。因此，了解是什么决定Treg细胞是否能够成功抑制其靶标，以及这在自身免疫性疾病和癌症中如何发挥作用是很重要的。我的研究重点是Src同源2结构域蛋白酪氨酸磷酸酶1 (SHP-1)，这是一种表征良好的tcr介导的信号传导负调节因子。利用三种不同的SHP-1缺乏症的遗传模型，我最近发现SHP-1调节了Tcon细胞对抑制的易感性，因此SHP-1缺乏症的Tcon细胞对wt treg介导的抑制表现出更高的抗性。在初步数据中，我已经证明来自母鼠的Tcon细胞，在所有造血细胞中缺乏SHP-1的表达，对treg介导的抑制具有抗性。我还在两种不同小鼠模型的Tcon细胞中观察到类似的耐药，携带T细胞特异性缺失SHP-1，表明SHP-1依赖性抗抑制是T细胞的内在效应。此外，用SHP-1药理学抑制剂stibogluconate钠（SSG）治疗小鼠，也使Tcon细胞对Treg介导的抑制产生抗性，进一步强化了SHP-1在调节Tcon细胞对Treg抑制易感性中的作用。有趣的是，SSG正处于实体肿瘤免疫治疗的I期临床试验中，但其抗肿瘤机制尚不清楚。这项拟议的研究将阐明SSG如何增强Tcon细胞抵抗treg介导的抑制的能力，并产生更有效的抗肿瘤反应。本研究将探讨SHP-1在细胞内信号通路水平以及自身免疫性疾病、炎症和抗肿瘤免疫模型中，在CD4+和CD8+ T细胞对Treg介导的抑制易感性中的作用。从这些研究中，我将确定可能的分子药物靶点，对其进行调节，要么诱导Tcon细胞对Treg抑制的敏感性，以治疗自身免疫性疾病，要么允许Tcon细胞抵抗Treg抑制，以治疗癌症。

DESCRIPTION (provided by applicant): The goal of this proposal is to understand the molecular mechanism that governs conventional T (Tcon) cell resistance to regulatory T cell (Treg)-mediated suppression and identify potential molecular targets for use in immunotherapy. Research over the past decade has demonstrated that Treg cells are a crucial component for a healthy immune system. Once activated through their T cell receptor (TCR), Treg cells can suppress a wide range of immune cells. It is becoming evident that in many autoimmune diseases, Treg cells remain functional, yet fail to control Tcon cells. At the same time, Treg cell hinder anti-tumor immunity by creating a suppressive tumor microenvironment. Therefore, it is important to understand what determines if a Treg cell is able to successfully suppress its target, and how this plays a role in both autoimmune disease and cancer. My research focuses on the Src homology 2 domain- containing protein tyrosine phosphatase 1 (SHP-1), a well-characterized negative regulator of TCR-mediated signaling. Using three different genetic models of SHP-1 deficiency, I have recently found that SHP-1 regulates the susceptibility of Tcon cells to suppression, such that SHP-1-deficient Tcon cells display increased resistance to wt Treg-mediated suppression. In preliminary data, I have shown that Tcon cells derived from motheaten mice, which lack SHP-1 expression in all hematopoietic cells, are resistant to Treg-mediated suppression. I also observed a comparable resistance in Tcon cells from two different mouse models, carrying a T cell specific deletion of SHP-1, indicating that the SHP-1-dependent resistance to suppression is a T cell-intrinsic effect. Moreover, treatment of mice with sodium stibogluconate (SSG), a pharmacological SHP-1 inhibitor, also rendered Tcon cells resistant to Treg-mediated suppression, further reinforcing the role of SHP-1 in regulating Tcon cell susceptibility to Treg suppression. Interestingly, SSG is in phase I clinical trials for solid tumo immunotherapy, yet its anti-tumor mechanism remains unclear. The proposed study will shed light on how SSG might be augmenting Tcon cells' ability to resist Treg-mediated suppression and mount a more effective anti-tumor response. This proposal will address the role of SHP-1 in CD4+ and CD8+ T cell susceptibility to Treg mediated suppression both at the level of intracellular signaling pathways as well as in vivo in models of autoimmune disease, inflammation, and anti-tumor immunity. From these studies, I will identify possible molecular drug targets, the modulation of which would either induce Tcon cell susceptibility to Treg-suppression for treatment of autoimmune disease, or allow Tcon cells to resist Treg suppression for treatment of cancer.