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(Tcon)细胞对调节性T细胞(Treg)介导的抑制的抗性的分子机制，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关键组成部分。一旦通过T细胞受体(TCR)激活，Treg细胞可以抑制多种免疫细胞。越来越明显的是，在许多自身免疫性疾病中，Treg细胞仍然具有功能，但无法控制Tcon细胞。同时，Treg细胞通过创造抑制性肿瘤微环境来阻碍抗肿瘤免疫。因此，重要的是要了解是什么决定了Treg细胞是否能够成功地抑制其靶点，以及这在自身免疫性疾病和癌症中如何发挥作用。我的研究重点是含有Src同源2结构域的蛋白酪氨酸磷酸酶1(SHP-1)，它是TCR介导的信号转导的一个很好的负调控因子。利用SHP-1缺乏的三种不同遗传模型，我最近发现SHP-1调节Tcon细胞对抑制的敏感性，从而使SHP-1缺陷的Tcon细胞对wt Treg介导的抑制表现出更高的抵抗力。在初步数据中，我已经表明，来自母鼠的Tcon细胞在所有造血细胞中都缺乏SHP-1的表达，对Treg介导的抑制具有抵抗力。我还在两种不同小鼠模型的Tcon细胞中观察到了类似的耐药性，携带着T细胞特异性的SHP-1缺失，表明SHP-1依赖的抑制抗性是T细胞固有的效应。此外，用药理上的SHP-1抑制剂硫代葡萄糖酸钠(SSG)处理小鼠，也使Tcon细胞对Treg介导的抑制产生抵抗，进一步加强了SHP-1在调节Tcon细胞对Treg抑制的敏感性中的作用。有趣的是，SSG正在进行固体肿瘤免疫治疗的I期临床试验，但其抗肿瘤机制尚不清楚。这项拟议的研究将阐明SSG可能如何增强Tcon细胞抵抗Treg介导的抑制和建立更有效的抗肿瘤反应的能力。本研究将在自身免疫性疾病、炎症和抗肿瘤免疫模型中，从细胞内信号通路水平和体内水平探讨SHP-1在CD4+和CD8+T细胞对Treg介导的抑制敏感性中的作用。从这些研究中，我将确定可能的分子药物靶点，这些靶点的调节将要么诱导Tcon细胞对用于治疗自身免疫性疾病的Treg抑制的敏感性，要么允许Tcon细胞抵抗用于治疗癌症的Treg抑制。

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.