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）：动物模型的研究表明，适应性和先天免疫系统在诱发肠道炎症方面都具有明确的作用，这是炎症性肠病的标志（IBD）。 TH-1和TH-17型T细胞在克罗恩病中具有主要作用，而TH-2型T细胞对于溃疡性结肠炎似乎更为重要。在过去的十年中，研究确定了调节性T细胞（T-REG）在控制IBD发展中的明确作用。 T-REGS是最近发现的CD4+ T细胞的子集，具有抑制辅助T细胞效应子功能的深刻能力。它们的特征是转录因子FOXP3和CD25的表达，同时是静止的。在细胞转移模型中，T-REG已显示可有效抑制IBD。然而，没有任何方法可以增强体内调节性T细胞的功能，该功能可能具有治疗潜力。 T-Regs表达CD5，一种细胞表面标记，主要存在于T细胞上，而B-1细胞的次要子集称为B-1细胞。基于我们先前关于CD5在B-1细胞中的负面信号传导作用的工作，我们假设CD5可能对T-REG细胞中的TCR信号负面调节。这预测，在没有CD5的情况下，可以增强T-REG的调节功能。因此，我们已经表明，来自CD5敲除小鼠的T-REG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，在硫酸葡萄酸盐（DSS）诱导的结肠炎模型中，CD5基因敲除小鼠具有较轻的疾病形式，我们假设这是由于更有效的NTREG功能。我们的具体目的是：1。我们的目标是首先证明CD5缺陷T-REG在收养转移模型中的有效性提高，该模型包括将CD45RB+ CD4+ CD25-T-cells转移到使用野生型或CD5敲除T-REGS的RAG1 - / - 小鼠中。 2。开发一种野生型动物模型，其中可以增强NTREG功能。在这里，我们将通过使用CD5-Ig融合蛋白和/或抗CD5抗体来抑制CD5与配体的相互作用来确定IBD的发展是否会降低。由于已知树突状细胞（DC）调节T-Regs的发育和功能，并且由于我们已证明CD5以调节TCR介导的钙信号传导，因此我们将测试以下假说，即通过CD5及其配体CD5L与T-Regs的相互作用相互作用会影响T-Reg功能。 3。开发一种替代结肠炎模型，以评估非T细胞在CD5 - / - 小鼠对结肠炎诱导的阳性抗性中的作用。我们已经发现，CD5通常在所有T细胞上表达，可降低调节性T细胞（T-REG）功能，并且来自CD5被遗传删除的小鼠的T-REGS是免疫反应的更有效的调节剂。在这里，我们计划证明，在疾病引起的T细胞诱导的结肠炎的体内动物模型中，T-Regs的功能受CD5表达的调节。