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

• 批准号: 7471782
• 负责人: SUBBARAO BONDADA
• 金额: $ 18.31万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 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/7471782
• 关键词: 5-(6)-carboxyfluorescein diacetate succinimidyl ester; 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' s disease; Dendritic Cells; Development; Dextran Sulfate; Disease; Effectiveness; Genus Cola; 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; day; in vivo; novel therapeutics; transcription factor

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，适应性和先天性免疫系统在诱导肠道炎症（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细胞在溃疡性结肠炎中似乎更重要。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细胞亚群是最近发现的CD 4 + T细胞亚群，其具有抑制辅助性T细胞的效应子功能的深刻能力。其特征在于表达转录因子Foxp 3和CD 25，同时处于静止状态。在细胞转移模型中，T-Reg已显示出有效抑制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-Reg表达CD 5，CD 5是一种主要存在于T细胞和称为B-1细胞的B-细胞的次要亚群上的细胞表面标志物。基于我们先前关于CD 5在B-1细胞中的负信号作用的工作，我们假设CD 5可能负调节T-reg细胞中的TCR信号传导。这预示着T-Regs的调节功能可以在不存在CD 5的情况下增强。因此，我们已经表明，来自CD 5敲除小鼠的T-Reg在抑制CD 4 + CD 25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，CD 5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。我们的具体目标是：1.我们的目标是首先证明在过继转移模型中CD 5缺陷型T-Reg的有效性增加，所述过继转移模型包括将CD 45 RB + CD 4 + CD 25-T细胞转移到具有野生型或CD 5敲除T-Reg的Rag 1-/-小鼠中。2.建立nTreg功能增强的野生型动物模型。在这里，我们将确定是否通过使用CD 5-IG融合蛋白和/或抗CD 5抗体抑制CD 5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）调节T-Reg的发育和功能，并且由于我们已经显示CD 5调节TCR介导的钙信号传导，因此我们将测试DC与T-Reg通过CD 5及其配体CD 5L的相互作用影响T-Reg功能的假设。3.建立结肠炎的替代模型，以评估非T细胞在CD 5-/-小鼠对结肠炎诱导的抵抗力增加中的作用。我们发现，CD 5（一种通常在所有T细胞上表达的分子）降低了调节性T细胞（T-reg）功能，并且来自CD 5基因缺失小鼠的T-reg是免疫应答的更有效调节剂。在这里，我们计划证明，在体内动物模型的结肠炎引起的疾病的T细胞，T-调节的功能是由CD 5的表达。