T regulatory cells in type I diabetes

I 型糖尿病中的 T 调节细胞

• 批准号: 8665416
• 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/8665416
• 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; Environmental Risk Factor; Epitopes; Exercise; Genetic Engineering; 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.

描述（由申请人提供）：I型糖尿病（T1D）是一种自发性疾病，其中免疫系统的细胞触发胰腺中的炎症，导致胰岛中产生胰岛素2个细胞的特定破坏。 CD4 T细胞对谷氨酸脱羧酶（GAD）或胰岛素2链（INS2）在T1D的表现中起主要作用。调节性T细胞（Tregs）通常能够控制糖尿病性T细胞并保持耐受性。然而，在易于疾病的小鼠中，例如非肥胖糖尿病（NOD）小鼠，以及在易感人类中，遗传和环境因素干扰Tregs的发育和/或功能，从而导致自动反应性T细胞的激活以及T1D的表现。最近，我们发现了一个新的T调节细胞种群，该细胞表达了FOXP3的中间水平（INT）水平，Tregs的特征转录因子和高水平的ROR3T，这是Th17细胞的签名转录因子。这些细胞（我们指定FOXP3INT）也表达CD62L，一种用于运输的分子，以及膜结合的TGF2，用于抑制效应T细胞。 FOXP3INT T细胞在疾病发育之前出现在脾脏T细胞库中，并在胰岛炎期间迁移到胰腺。 IG-GAD1是一种基因设计的IG-GAD1，用于表达GAD的糖尿病性524-543表位，可扩展Foxp3Int T细胞而不会引起进一步的分化。实际上，转移到点头后，Ig-GAD1扩展的FOXP3INT T细胞会迁移到胰腺。SCID小鼠的受益者受糖尿病性T细胞的接受者并抑制效应T细胞，同时保留FOXP3INT和ROR3T的双重表达。该提案中要检验的主要假设假设A）。 FOXP3INT T细胞代表胸腺衍生的表达FoxP3的过渡中间体，可在与自抗原的非炎性相遇下脾脏上调ROR3T和MTGF2。 b）。这些细胞在胰岛炎前阶段很容易通过IG-GAD1扩展，并在胰岛炎阶段有效地迁移到胰腺，在那里它们对糖尿病发挥广泛的抑制作用。 c）。脾脏中与循环效应T细胞的相互作用会导致MTGF2和D的损失。较高剂量的IG-GAD1的扩展注射可能会胜过这些相互作用，并扩大可能在该疾病晚期阶段逆转T1D的FOXP3INT T细胞。提出了三个目的来检验这一假设。 AIM ONE将测试扩展的IG-GAD1方案，以在T1D的高级阶段扩展FoxP3Int Treg。此外，此目标将测试FOXP3INT T细胞作为晚期T1D糖尿病的细胞疗法，并确定它们是否起源于胸腺天然Treg。 AIM 2将定义抗原特异性在FOXP3INT T细胞的扩展和功能中的作用，而AIM 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TREG的出现和抑制如何产生可用于预防和逆转疾病的信息。