T regulatory cells in type I diabetes

I 型糖尿病中的 T 调节细胞

• 批准号: 8214278
• 负责人: HABIB ZAGHOUANI
• 金额: $ 31.98万
• 依托单位: UNIVERSITY OF MISSOURI-COLUMBIA
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-05-01 至 2016-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8214278
• 关键词: Antigen-Presenting Cells; Antigens; Autoantigens; Autoimmunity; Basic Science; Binding; Bystander Suppression; CD4 Positive T Lymphocytes; Cell Differentiation process; Cell physiology; Cells; Clinical; Development; Diabetes Mellitus; Disease; Dose; Engineering; Environmental Risk Factor; Epitopes; Exercise; Glutamate Decarboxylase; Human Genetics; Immune system; Inbred NOD Mice; Inflammation; Inflammatory; Injection of therapeutic agent; Insulin; Insulin-Dependent Diabetes Mellitus; Investigation; Islets of Langerhans; Lymphocyte; Mediating; Membrane Protein Traffic; Mus; Non obese; Pancreas; Peptides; Play; Population; Prevention; Regimen; Regulatory T-Lymphocyte; Role; SELL gene; Specificity; Spleen; Staging; System; T-Cell Immunologic Specificity; T-Lymphocyte; Testing; Treatment Protocols; autoreactive T cell; cytokine; design; diabetic; novel; receptor; transcription factor

DESCRIPTION (provided by applicant): Type I diabetes (T1D) is a spontaneous disease in which cells of the immune system trigger inflammation in the pancreas leading to a specific destruction of the insulin-producing 2 cells within the pancreatic islets. CD4 T cells specific for glutamic acid decarboxylase (GAD) or insulin 2 chain (INS2) play a major role in the manifestation of T1D. Regulatory T cells (Tregs) are usually able to control the diabetogenic T cells and maintain tolerance. However, in disease prone mice, such as the non-obese diabetic (NOD) mouse, and in susceptible humans, genetic and environmental factors interfere with the development and/or function of Tregs, leading to activation of autoreactive T cells and manifestation of T1D. Recently, we discovered a novel population of T regulatory cells that expresses intermediate (int) levels of FoxP3, the signature transcription factor for Tregs, and high level of ROR3t, the signature transcription factor for Th17 cells. These cells, which we designate FoxP3int, also express CD62L, a molecule used for trafficking, and membrane-bound TGF2 which is utilized for suppression of effector T cells. FoxP3int T cells arise in the splenic T cell repertoire prior to disease development and migrate to the pancreas during insulitis. Ig-GAD1, an Ig molecule genetically engineered to express the diabetogenic 524-543 epitope of GAD, expands FoxP3int T cells without causing further differentiation. In fact, Ig-GAD1-expanded FoxP3int T cells migrate to the pancreas upon transfer into NOD.scid mice recipient of diabetogenic T cells and suppress the effector T cells while preserving dual expression of FoxP3int and ROR3t. The major hypothesis to be tested in this proposal postulates that a). FoxP3int T cells represent thymic derived FoxP3-expressing transitional intermediates that up-regulate ROR3t and mTGF2 in the spleen under non inflammatory encounters with self-antigen. b). the cells are readily expandable with Ig-GAD1 at the pre-insulitis stage and effectively migrate to the pancreas at the insulitis stage where they exercise broad suppressive function against diabetes. c). interaction with circulating effector T cells in the spleen leads to loss of mTGF2 and d). extended injection of higher doses of Ig-GAD1 will likely outcompete those interactions and expand FoxP3int T cells that could reverse T1D at advanced stages of the disease. Three aims are proposed to test this hypothesis. Aim one will test extended Ig-GAD1 regimens for expansion of FoxP3int Tregs at advanced stages of T1D. Also this aim will test FoxP3int T cells as a cellular therapy for advanced T1D diabetes and determine whether they originate from thymic natural Tregs. Aim 2 will define the role of antigen-specificity in the expansion and function of FoxP3int T cells and aim 3 will determine whether mTGF2 expression on FoxP3int T cells is regulated by effector T cells. Understanding how Tregs arise and suppress T1D could yield information useful for prevention and reversal of the disease. PUBLIC HEALTH RELEVANCE: The study proposed in this application will investigate antigen-specific mechanisms underlying expansion of regulatory T cells and suppression of type I diabetes. A novel population of FoxP3 regulatory T cells has been identified and understanding how these suppressive T cells function and interact with diabetogenic effector lymphocytes should yield information useful for the design of approaches to protect against the disease. Also, the approach takes advantage of an unique peptide delivery system that is adaptable for investigation of novel mechanistic aspects of Treg development and function. The study could impact the field of type I diabetes and autoimmunity both at the basic science and clinical levels.

描述（由申请人提供）：I 型糖尿病 (T1D) 是一种自发性疾病，其中免疫系统细胞触发胰腺炎症，导致胰岛内产生胰岛素的 2 细胞发生特异性破坏。谷氨酸脱羧酶 (GAD) 或胰岛素 2 链 (INS2) 特异性的 CD4 T 细胞在 T1D 的表现中发挥着重要作用。调节性 T 细胞 (Treg) 通常能够控制致糖尿病 T 细胞并维持耐受性。然而，在易患病小鼠（例如非肥胖糖尿病 (NOD) 小鼠）和易感人类中，遗传和环境因素干扰 Tregs 的发育和/或功能，导致自身反应性 T 细胞激活和 T1D 表现。最近，我们发现了一个新的 T 调节细胞群，它们表达中等 (int) 水平的 FoxP3（Treg 的标志性转录因子）和高水平的 ROR3t（Th17 细胞的标志性转录因子）。这些细胞（我们将其命名为 FoxP3int）还表达 CD62L（一种用于运输的分子）和膜结合的 TGF2（用于抑制效应 T 细胞）。 FoxP3int T 细胞在疾病发展之前出现在脾 T 细胞库中，并在胰岛炎期间迁移到胰腺。 Ig-GAD1 是一种经过基因工程改造的 Ig 分子，可表达 GAD 的致糖尿病 524-543 表位，可扩增 FoxP3int T 细胞而不引起进一步分化。事实上，Ig-GAD1 扩增的 FoxP3int T 细胞在转移到接受糖尿病 T 细胞的 NOD.scid 小鼠体内后，会迁移到胰腺，并抑制效应 T 细胞，同时保留 FoxP3int 和 ROR3t 的双重表达。本提案中要检验的主要假设假设 a)。 FoxP3int T 细胞代表胸腺来源的表达 FoxP3 的过渡中间体，在与自身抗原的非炎症接触下上调脾脏中的 ROR3t 和 mTGF2。 b).在胰岛炎前期，这些细胞很容易通过 Ig-GAD1 进行扩增，并在胰岛炎阶段有效地迁移到胰腺，在胰岛炎阶段发挥广泛的糖尿病抑制功能。 c).与脾脏中循环效应 T 细胞的相互作用导致 mTGF2 和 d) 的损失。延长注射更高剂量的 Ig-GAD1 可能会战胜这些相互作用，并扩大 FoxP3int T 细胞，从而逆转疾病晚期的 T1D。提出了三个目标来检验这一假设。目标一将测试延长的 Ig-GAD1 治疗方案，以在 T1D 晚期阶段扩展 FoxP3int Tregs。此外，该目标还将测试 FoxP3int T 细胞作为晚期 T1D 糖尿病的细胞疗法，并确定它们是否源自胸腺天然 Tregs。目标 2 将定义抗原特异性在 FoxP3int T 细胞扩增和功能中的作用，目标 3 将确定 FoxP3int T 细胞上的 mTGF2 表达是否受效应 T 细胞调节。了解 Tregs 如何产生和抑制 T1D 可以提供有助于预防和逆转该疾病的信息。 公共健康相关性：本申请中提出的研究将调查调节性 T 细胞扩增和抑制 I 型糖尿病的抗原特异性机制。已经鉴定出一种新的 FoxP3 调节性 T 细胞群，了解这些抑制性 T 细胞如何发挥作用并与致糖尿病效应淋巴细胞相互作用，应该会产生有助于设计预防该疾病的方法的信息。此外，该方法利用了独特的肽递送系统，该系统适用于研究 Treg 发育和功能的新机制。这项研究可能会在基础科学和临床层面影响 I 型糖尿病和自身免疫领域。