Importance of CD5 for the function of regulatory T cells

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导肠道炎症（炎症性肠病（IBD）的标志）中都有明确的作用。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-regs是最近发现的CD4+ T细胞的一个亚群，具有抑制辅助T细胞效应功能的深刻能力。它们的特点是在静止状态下表达转录因子Foxp3和CD25。在细胞转移模型中，T-Regs已被证明能有效抑制IBD。然而，目前还没有任何方法可以在体内增强调节性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细胞和少量B细胞（称为B-1细胞）上的细胞表面标记物。基于我们之前关于CD5在B-1细胞中的负信号作用的研究，我们假设CD5可能负调控T-reg细胞中的TCR信号。这预示着T-Regs的调控功能可以在缺乏CD5的情况下增强。因此，我们已经证明来自CD5敲除小鼠的T- regs更有效地抑制CD4+CD25效应T细胞的增殖。此外，我们的初步研究表明，在葡聚糖硫酸盐（DSS）诱导的结肠炎模型中，CD5敲除小鼠的疾病形式较轻，我们假设这是由于更有效的nTreg功能。我们的具体目标是：1。我们的目标是首先在过继转移模型中证明CD5缺陷T-Regs的有效性，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-Regs的Rag1-/-小鼠中。2. 建立一种能增强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。由于树突状细胞（DC）已知可以调节T-Regs的发育和功能，并且CD5已经被我们证明可以调节TCR介导的钙信号传导，我们将测试DC通过CD5及其配体CD5L与T-Regs相互作用影响t - regg功能的假设。3. 建立结肠炎的替代模型，以评估非T细胞在CD5-/-小鼠对结肠炎诱导的抗性增加中的作用。我们已经发现，CD5（一种通常在所有T细胞上表达的分子）降低调节性T细胞（T-reg）功能，并且来自CD5基因缺失小鼠的T-reg是免疫反应的更有效调节剂。在这里，我们计划证明在由疾病引起的T细胞诱导的结肠炎的体内动物模型中，T- regs的功能受到CD5表达的调节。

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.