Exploring Regulatory T Cell Dysfunction in a Murine Model of Colitis

探索小鼠结肠炎模型中的调节性 T 细胞功能障碍

• 批准号: 8415867
• 负责人: Scott B Snapper
• 金额: $ 32.38万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-04-05 至 2015-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8415867
• 关键词: Adoptive Transfer; Affect; Animals; Antigens; Autoimmunity; Automobile Driving; CD4 Positive T Lymphocytes; Cell Surface Receptors; Cells; Chronic; Colitis; Cytokine Signaling; Cytoskeletal Modeling; Cytoskeleton; Data; Defect; Dendritic Cells; Development; Disease; Functional disorder; Gene Expression; Generations; Genes; Genetic; Genetic Transcription; Goals; Health; Hematopoietic; Homing; Human; IL2RA gene; Immune; Immune system; Immunologic Deficiency Syndromes; Inflammation; Inflammatory Bowel Diseases; Integrins; Interleukin-13; Interleukin-2; Interleukin-4; Investigation; Knockout Mice; Knowledge; Lamina Propria; Lead; Leukocytes; Link; Lymphocyte; Mediating; Modeling; Molecular; Mucosal Immunity; Mus; Names; Onset of illness; Pathogenesis; Patients; Penetrance; Population; Protein Deficiency; Proteins; Receptor Signaling; Regulation; Regulatory T-Lymphocyte; Relative (related person); Role; Signal Transduction; Signaling Molecule; Site; T-Cell Receptor; T-Lymphocyte; Testing; Thymus Gland; Tissues; Wiskott-Aldrich Syndrome; arm; base; cell motility; chemokine receptor; congenital immunodeficiency; cytokine; design; immunological synapse; imprint; in vivo; migration; mouse model; receptor-mediated signaling; research study; synaptogenesis

DESCRIPTION (provided by applicant): The overall goal of this project is to gain further understanding of the mucosal immune system and the defects that contribute to the pathogenesis of human inflammatory bowel disease (IBD). The generation of a number of murine models of IBD has facilitated investigation into the basic mechanisms underlying IBD pathogenesis. Despite the fact that many murine models of IBD result from a defect in a single protein known to affect leukocyte function, the specific auto-reactive and/or regulatory cell population responsible for disease pathogenesis in these models remains unknown. We recently generated a mouse model of IBD that results from the targeted disruption of the Wiskott-Aldrich syndrome protein (WASP). WASP is expressed solely in hematopoietic cells and is a signaling molecule that regulates cell surface receptor signals to the cytoskeleton. Abnormalities in this protein lead to the rare X-linked primary immunodeficiency that carries its name. Autoimmunity is commonly associated with this immunodeficiency, and up to 10 percent of patients develop an IBD-like illness. Our lab has recently shown that 100% of WASP KO (WKO) mice also develop colitis. Genetic and adoptive transfer studies have shown that lymphocytes are essential and CD4+ lymphocytes are sufficient for colitis development. In contrast with most murine models of IBD that have a Th1 bias, we have demonstrated a Th2 cytokine skewing (with elevated IL-4 and IL-13) in lamina propria (LP) lymphocytes and in tissues. Indeed, IL-4 is required, at least in part, for colitis development. Perhaps, most interestingly, we have recently shown that there is marked reduction in the development and function of regulatory T cells in WKO animals. Our overall hypothesis is that the colitis in WKO mice results from both intrinsic Treg dysfunction as well as extrinsic signaling/cytokine abnormalities within the CD4+ T cell/APC population that results in Treg dysfunction. In this proposal we seek to determine the cellular and molecular basis for colitis development and autoimmunity in WKO mice. Aim 1 seeks to uncover the mechanism(s) (development, migration, and cell-cell contacts) that are responsible for the aberrant Treg development and dysfunction in WKO mice. Aim 2 seeks to assess the impact of WASP deficiency in innate immune cells on the generation and function of Tregs. Aim 3 seeks to determine the role of WASP-dependant T cell receptor (TCR) signaling and aberrant cytokine secretion on Treg dysfunction. The overall goal of this proposal is to further our understanding of the mechanism of colitis in WKO mice that is uniquely associated with both profound regulatory T cell defects and Th2 cytokine skewing and to take advantage of a murine model of colitis that uniquely has a human correlate. Our driving premise is that such knowledge will not only aid in the understanding and treatment of the debilitating autoimmunity (and IBD-like illness) that characterizes the human immunodeficiency but will also aid in our understanding of mucosal immune regulation in general and the molecular underpinnings of inflammatory bowel disease.

描述（由申请人提供）：该项目的总体目标是进一步了解粘膜免疫系统以及导致人类炎症性肠病（IBD）发病机制的缺陷。许多IBD小鼠模型的产生促进了对IBD发病机制的基本机制的研究。尽管许多 IBD 小鼠模型是由已知影响白细胞功能的单一蛋白质缺陷引起的，但在这些模型中负责疾病发病机制的特定自身反应和/或调节细胞群仍然未知。我们最近建立了一种 IBD 小鼠模型，该模型是由 Wiskott-Aldrich 综合征蛋白 (WASP) 的靶向破坏引起的。 WASP 仅在造血细胞中表达，是调节细胞表面受体向细胞骨架发出信号的信号分子。这种蛋白质的异常会导致罕见的 X 连锁原发性免疫缺陷病，该病也因此得名。自身免疫通常与这种免疫缺陷有关，高达 10% 的患者会出现类似 IBD 的疾病。我们的实验室最近表明，100% 的 WASP KO (WKO) 小鼠也会患上结肠炎。遗传和过继转移研究表明，淋巴细胞对于结肠炎的发展至关重要，并且 CD4+ 淋巴细胞足以形成结肠炎。与大多数具有 Th1 偏好的 IBD 小鼠模型相比，我们在固有层 (LP) 淋巴细胞和组织中证明了 Th2 细胞因子偏向（IL-4 和 IL-13 升高）。事实上，IL-4 是结肠炎发展所必需的，至少是部分必需的。也许，最有趣的是，我们最近发现 WKO 动物中调节性 T 细胞的发育和功能显着减少。我们的总体假设是，WKO 小鼠的结肠炎是由内在 Treg 功能障碍以及 CD4+ T 细胞/APC 群体内导致 Treg 功能障碍的外在信号/细胞因子异常引起的。在本提案中，我们试图确定 WKO 小鼠结肠炎发展和自身免疫的细胞和分子基础。目标 1 试图揭示导致 WKO 小鼠 Treg 异常发育和功能障碍的机制（发育、迁移和细胞间接触）。目标 2 旨在评估先天免疫细胞中 WASP 缺陷对 Tregs 的生成和功能的影响。目标 3 旨在确定 WASP 依赖性 T 细胞受体 (TCR) 信号传导和异常细胞因子分泌对 Treg 功能障碍的作用。该提案的总体目标是进一步了解 WKO 小鼠结肠炎的机制，该机制与深度调节性 T 细胞缺陷和 Th2 细胞因子偏差独特相关，并利用与人类独特相关的小鼠结肠炎模型。我们的驱动前提是，这些知识不仅有助于理解和治疗人类免疫缺陷所特有的衰弱性自身免疫（和炎症性肠病样疾病），而且还有助于我们了解粘膜免疫调节的一般情况和分子基础。炎症性肠病。

项目成果

Inflammatory bowel disease and mutations affecting the interleukin-10 receptor.

• DOI: 10.1056/nejmoa0907206
• 发表时间: 2009-11-19
• 期刊: The New England journal of medicine
• 作者: Glocker EO;Kotlarz D;Boztug K;Gertz EM;Schäffer AA;Noyan F;Perro M;Diestelhorst J;Allroth A;Murugan D;Hätscher N;Pfeifer D;Sykora KW;Sauer M;Kreipe H;Lacher M;Nustede R;Woellner C;Baumann U;Salzer U;Koletzko S;Shah N;Segal AW;Sauerbrey A;Buderus S;Snapper SB;Grimbacher B;Klein C
• 通讯作者: Klein C

Variants in TRIM22 That Affect NOD2 Signaling Are Associated With Very-Early-Onset Inflammatory Bowel Disease.

• DOI: 10.1053/j.gastro.2016.01.031
• 发表时间: 2016-05
• 期刊: Gastroenterology
• 影响因子: 29.4
• 作者: Li Q;Lee CH;Peters LA;Mastropaolo LA;Thoeni C;Elkadri A;Schwerd T;Zhu J;Zhang B;Zhao Y;Hao K;Dinarzo A;Hoffman G;Kidd BA;Murchie R;Al Adham Z;Guo C;Kotlarz D;Cutz E;Walters TD;Shouval DS;Curran M;Dobrin R;Brodmerkel C;Snapper SB;Klein C;Brumell JH;Hu M;Nanan R;Snanter-Nanan B;Wong M;Le Deist F;Haddad E;Roifman CM;Deslandres C;Griffiths AM;Gaskin KJ;Uhlig HH;Schadt EE;Muise AM
• 通讯作者: Muise AM