Role of Regulatory T cells in GVHD, GVT, and Tolerance Induction

项目总结（见说明）：PrOJeCt 3 免疫反应的调节在健康和疾病中至关重要。这一点在异基因造血细胞移植（HCT）之后最为清楚，其中诱导有效的免疫应答消除了移植物抗肿瘤（GVT）效应中的残留疾病，而针对宿主的异常免疫反应可导致危及生命的移植物抗宿主病（GVHD）。我们和其他人已经发现，CD4+CD25+FoxP3+调节性T细胞（Treg）能够控制GVHD，但允许GVT效应并促进更有效的免疫重建。在这项提案中，我们将在最初资助期间取得广泛进展的基础上，研究Treg控制GVHD反应的机制的关键生物学特征。我们已经开发了利用生物发光（BLl）的新型成像技术，其允许我们连续且非侵入性地研究包括Treg的不同细胞群体的运输和存活。 我们的假设是Treg运输到关键节点位点，在那里它们与抗原呈递细胞（APC）相互作用，并通过这种相互作用下调效应CD4+和CD8+同种异体反应性T细胞的增殖。在本提案中，我们将研究Treg和CD11C+ APC之间的相互作用的作用，通过选择性地从受体动物中消耗后者群体。我们将评估Treg表达的关键分子在这一过程中的作用，并探讨与APC的相互作用以及Treg介导的免疫调节中细胞表面受体和酶的表达的重要性。使用BL1和我们实验室开发的新型转基因小鼠系，我们将探索Treg利用的机制，包括运输到关键位点、增殖和控制同种异体反应性T细胞扩增。我们还将利用本基金初始阶段产生的数据，探索在体外和体内扩增Treg的新方法。特别是，我们已经证明了Treg在活化时利用与常规CD4+ T细胞不同的信号传导途径，并且我们将探索在活体动物和培养物中扩增Treg的方法。我们期望这些研究将显著增加我们对Treg在HCT和器官移植中的生物学和机制的基本理解。

PROJECT SUMMARY (See instructions): PrOJeCt 3 Regulation of immune responses is critical in health and disease. Nowhere is this clearer than following allogeneic hematopoietic cell transplantation (HCT) where induction of effective immune responses eliminates residual disease in the graft vs tumor (GVT) effect, whereas an aberrant immune reaction towards the host can result in life threatening graft vs host disease (GVHD). We and others have found that CD4+CD25+FoxP3+ regulatory T cells (Treg) are capable of controlling GVHD yet allow for GVT effects and promote more effective immune reconstitution. In this proposal we will build upon extensive progress in the initial funding period to study critical biological characteristics of the mechanisms by which Treg control GVHD reactions. We have developed novel imaging technology utilizing bioluminescence (BLl) that allows us to serially and non-invasively study the trafficking and survival of distinct cell populations including Treg. Our hypothesis is that Treg traffic to critical nodal sites where they interact with antigen presenting cells (APCs) and through this interaction down modulate the proliferation of effector CD4+ and CD8+ alloreactive T cells. In this proposal we will study the role of the interaction between Treg and CD11C+ APCs by selectively depleting this latter population from recipient animals. We will evaluate the role of critical molecules expressed by Treg in this process and explore the importance of interaction with APCs and expression of cell surface receptors and enzymes in immune regulation mediated by Treg. Using BLl and novel transgenic mouse lines developed in our laboratories we will explore mechanisms utilized by Treg including trafficking to critical sites, proliferation and control of alloreactive T cell expansion. We will also utilize data generated in the initial term of this grant to explore novel approaches to expanding Treg both in vitro and in vivo. In particular we have demonstrated the Treg utilize different signaling pathways upon activation than conventional CD4+ T cells and we will explore approaches to the expansion of Treg both in living animals and in cultures. We expect that these studies will significantly increase our basic understanding of the biology and mechanisms of Treg in the settings of HCT and organ transplantation.