Mechanisms of Peripheral CD4 T-cells tolerance

本项目的总体目标是确定CD 4 T细胞的细胞和分子机制， 对系统性自身抗原的耐受性。这些研究将检验T细胞中的细胞内在耐受性 由近端信号传导阻滞和不平衡的细胞因子产生的组合引起，并且当 无反应性和缺失的细胞内在机制失败，在没有其他刺激的情况下延长自身抗原识别 可能导致调节性T细胞的逐步发育。这些研究将依赖于一个完善的 系统性T细胞耐受的转基因模型具有一些独特的优势，特别是它是顺从的， 对遇到自身抗原的细胞进行生物化学和分子分析，这是唯一的系统， 其中从单克隆T细胞群依次产生效应T细胞和调节T细胞， 对外周组织中自身抗原识别的应答。将处理以下具体目标： 1.系统性自身抗原诱导的细胞内在耐受（无反应性和缺失）的机制。 这些研究将确定识别系统性自身抗原导致无反应性的T细胞中的信号传导阻滞 在体内，使用一种新的多重磷蛋白阵列和其他技术，并检查已知的作用， T细胞调节因子（CTLA-4、Fas、Bim）在系统耐受中的作用。此外，本研究还将探讨小说的构思 没有IL-2的IFN-γ的不平衡产生有助于T细胞耐受，并定义了机制 这是IFN-γ作为耐受诱导细胞因子的这种意想不到的作用的基础。 2.外周产生的调节性T细胞（Treg）的诱导和功能。使用模型 响应于系统性抗原的识别，效应T细胞和Treg的顺序发育，这些 研究将确定这两种细胞群之间的谱系关系以及细胞因子在 控制效应细胞和调节细胞之间的平衡。亲本对F_1代移植物抗宿主反应的模型 将被用来检查多克隆T细胞的情况下，效应和调节T细胞的发展 反应性 因此，该项目使用了一个确定的实验系统和各种精确的分析方法， 研究外周T细胞耐受的基本机制，其诱导和维持， 外部信号的调节。这个项目之间有许多密切的互动， CTLA-4和Treg的研究，信号通路，中枢和 外周耐受机制这些结果不仅具有生物学意义，而且还将提供 作为一种治疗方式，诱导耐受的策略有价值的线索。

The overall objective of this project is to define the cellular and molecular mechanisms of CD4 T-cell tolerance to a systemic self-antigen. The studies will test the hypotheses that cell-intrinsic tolerance in T-cells results from a combination of proximal signaling blocks and imbalanced cytokine production, and when the cell-intrinsic mechanisms of anergy and deletion fail, prolonged self-antigen recognition without other stimuli may lead to progressive development of regulatory T-cells. The studies will rely on a well-established transgenic model of systemic T-cell tolerance which has some unique strengths, notably that it is amenable to biochemical and molecular analyses of cells that have encountered self-antigen, and it is the only system in which effector and regulatory T-cells are generated sequentially from a monoclonal T-cell population in response to self-antigen recognition in peripheral tissues. The following specific aims will be addressed: 1. Mechanisms of cell-intrinsic tolerance (anergy and deletion) induced by a systemic self-antigen. These studies will define signaling blocks in T-cells rendered anergic by recognition of systemic self-antigen in vivo, using a novel multiplex phosphoprotein array and other techniques, and examine the roles of known T-cell regulators (CTLA-4, Fas, Bim) in systemic tolerance. In addition, the studies will explore the novel idea that imbalanced production of IFN-y without IL-2 contributes to T-cell tolerance, and define the mechanisms underlying this unexpected role of IFN-y as a tolerance-inducing cytokine. 2. Induction and functions of peripherally generated regulatory T-cells (Treg). Using a model of sequential development of effector T-cells and Treg in response to recognition of systemic antigen, these studies will define the lineage relationships between these two cell populations and the roles of cytokines in controlling the balance between effector and regulatory cells. A model of parent to F1 graft-vs-host reaction will be used to examine the development of effector and regulatory T-cells in situations of polyclonal T-cell reactivity. Thus, this project uses a defined experimental system and a variety of precise analytical methods to study fundamental mechanisms of peripheral T-cell tolerance, its induction and maintenance, and its regulation by external signals. There are numerous close interactions between this project and studies of CTLA-4 and Treg, signaling pathways, interactions of central and peripheral tolerance mechanisms. The results are not only of biological significance, but will also provide valuable leads for strategies to induce tolerance as a therapeutic modality.