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Importance of CD5 for the function of regulatory T cells

CD5 对于调节性 T 细胞功能的重要性

基本信息

批准号：
7640703
负责人：
SUBBARAO BONDADA
金额：
$ 21.98万
依托单位：
UNIVERSITY OF KENTUCKY
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-06-17 至 2010-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7640703
关键词：
Adoptive Transfer Affect Animal Model Antibodies Antigen-Presenting Cells B-Lymphocyte Subsets B-Lymphocytes CD4 Positive T Lymphocytes Calcium Signaling Cell physiology Cell surface Cells Characteristics Chimeric Proteins Colitis Colon Crohn&apos s disease Dendritic Cells Development Dextran Sulfate Disease Effectiveness Goals Helper-Inducer T-Lymphocyte Human IL2RA gene Immune Immune response Immune system Inflammatory Inflammatory Bowel Diseases Inflammatory disease of the intestine Investigation Knock-out Knockout Mice Label Ligands Mediating Methods Minor Modeling Molecular Target Mus Public Health Rag1 Mouse Receptor Signaling Resistance Role Signal Transduction Sulfonic Acids T-Cell Receptor T-Lymphocyte TCR Activation Testing Therapeutic Trinitrobenzenes Ulcerative Colitis Work base combat in vivo novel therapeutic intervention transcription factor

项目摘要

DESCRIPTION (provided by applicant): Studies in animal models have shown that both the adaptive and the innate immune system have a definite role in inducing intestinal inflammation, a hallmark of inflammatory bowel diseases (IBD). The Th-1 and Th-17 type T cells have a dominant role in Crohn's disease while the Th-2 type T cells appear to be more important for ulcerative colitis. Studies in the past decade have established the unequivocal role of regulatory T cells (T-Reg) in controlling the development of IBD. The T-regs are a recently discovered subset of CD4+ T cells that have a profound ability to suppress the effector function of helper T cells. They are characterized by expression of a transcription factor Foxp3 and CD25, while being quiescent. In cell transfer models T-Regs have been shown to potently suppress IBD. Yet there have not been any methods to augment the function of regulatory T cells in vivo which could have therapeutic potential. T-Regs express CD5, a cell surface marker present primarily on T cells and a minor subset of B- cells called B-1 cells. Based on our previous work about the negative signaling role of CD5 in B-1 cells we hypothesized that CD5 might negatively regulate TCR signaling in T-reg cells. This predicted that the regulatory function of T-Regs can be augmented in the absence of CD5. Accordingly we have shown that T-Regs from CD5 knockout mice are more effective in suppressing proliferation of CD4+CD25- effector T cells. Moreover, our preliminary studies showed that in the dextran sulfate (DSS) induced model of colitis, CD5 knockout mice have a milder form of the disease which we hypothesize is due to more effective nTreg function. Our specific aims are: 1. Our goal is to first to demonstrate the increased effectiveness of CD5 deficient T- Regs in an adoptive transfer model that consists in transferring CD45RB+ CD4+ CD25- T-cells into Rag1-/- mice with wild type or CD5 knockout T-Regs. 2. To develop a wild type animal model in which nTreg function can be enhanced. Here we will determine if development of IBD is reduced by inhibiting interaction of CD5 with its ligand using a CD5-Ig fusion protein and/or anti-CD5 antibodies. Since dendritic cells (DC) are known to modulate the development and function of T-Regs and since CD5 has been shown by us to regulate TCR mediated calcium signaling, we will test the hypothesis that interaction of DC with T-Regs via CD5 and its ligand CD5L, affects T-reg function. 3. To develop an alternate model of colitis to evaluate the role of non T cells in the inreased resistance of CD5-/- mice to colitis induction. PUBLIC HEALTH RELEVACE We have found that CD5, a molecule generally expressed on all T cells, decreases regulatory T cell (T-reg) function and that T-Regs from mice in which CD5 is genetically deleted are more potent regulators of immune response. Here we plan to demonstrate that in an in vivo animal model of colitis induced by disease causing T cells, the function of T-Regs is regulated by CD5 expression.

描述（由申请人提供）：动物模型研究表明，适应性免疫系统和先天免疫系统在诱发肠道炎症（炎症性肠病（IBD）的标志）方面具有明确的作用。 Th-1 和 Th-17 型 T 细胞在克罗恩病中起主导作用，而 Th-2 型 T 细胞似乎对溃疡性结肠炎更重要。过去十年的研究已经确定了调节性 T 细胞 (T-Reg) 在控制 IBD 发展中的明确作用。 T-reg 是最近发现的 CD4+ T 细胞亚群，具有抑制辅助 T 细胞效应功能的强大能力。它们的特点是表达转录因子 Foxp3 和 CD25，同时处于静止状态。在细胞转移模型中，T-Regs 已被证明可以有效抑制 IBD。然而，目前还没有任何方法可以增强体内调节性 T 细胞的功能，从而具有治疗潜力。 T-Regs 表达 CD5，这是一种主要存在于 T 细胞和称为 B-1 细胞的一小部分 B 细胞上的细胞表面标记。基于我们之前关于 B-1 细胞中 CD5 负信号传导作用的研究，我们假设 CD5 可能负向调节 T-reg 细胞中的 TCR 信号传导。这预示着 T-Regs 的调节功能可以在 CD5 缺失的情况下得到增强。因此，我们已经证明来自 CD5 敲除小鼠的 T-Regs 在抑制 CD4+CD25- 效应 T 细胞的增殖方面更有效。此外，我们的初步研究表明，在硫酸葡聚糖 (DSS) 诱导的结肠炎模型中，CD5 敲除小鼠的疾病较轻，我们推测这是由于更有效的 nTreg 功能所致。我们的具体目标是： 1. 我们的目标是首先在过继转移模型中证明 CD5 缺陷 T-Reg 的有效性增加，该模型包括将 CD45RB+ CD4+ CD25- T 细胞转移到具有野生型或 CD5 敲除 T-Reg 的 Rag1-/- 小鼠中。 2. 建立可增强nTreg功能的野生型动物模型。在这里，我们将确定是否通过使用 CD5-Ig 融合蛋白和/或抗 CD5 抗体抑制 CD5 与其配体的相互作用来减少 IBD 的发展。由于已知树突状细胞 (DC) 可以调节 T-Reg 的发育和功能，并且我们已证明 CD5 可以调节 TCR 介导的钙信号传导，因此我们将测试 DC 通过 CD5 及其配体 CD5L 与 T-Reg 相互作用影响 T-reg 功能的假设。 3. 开发另一种结肠炎模型，以评估非 T 细胞在 CD5-/- 小鼠对结肠炎诱导抵抗力增强中的作用。公共健康相关我们发现，CD5（一种普遍在所有 T 细胞上表达的分子）会降低调节性 T 细胞 (T-reg) 功能，而来自基因删除 CD5 的小鼠的 T-Reg 是更有效的免疫反应调节剂。在这里，我们计划证明，在由致病 T 细胞诱导的结肠炎体内动物模型中，T-Regs 的功能受到 CD5 表达的调节。