Mechanisms of Peripheral CD4 T-cells tolerance

这个项目的总体目标是确定CD4T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细胞内在耐受性的假设 这是近端信号传导阻断和细胞因子产生不平衡的结果，当 无能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细胞的进行性发展。这些研究将依赖于一项成熟的 系统性T细胞耐受的转基因模型，具有一些独特的优点，特别是它是可屈从的 对遇到自身抗原的细胞进行生化和分子分析，这是唯一的系统 其中效应器和调节性T细胞是从单克隆性T细胞群中顺序产生的 周围组织对自身抗原识别的反应。将实现以下具体目标： 1.系统自身抗原诱导细胞内源性耐受(无能和缺失)的机制。 这些研究将确定通过识别系统自身抗原而变得无能的T细胞中的信号阻断 在体内，利用一种新颖的多重磷蛋白阵列等技术，并检查已知的作用 T细胞调节因子(CTLA-4、Fas、Bim)与全身耐受此外，这些研究还将探索新的想法 缺乏IL-2的干扰素-γ的不平衡产生有助于T细胞耐受，并确定了其机制 作为一种诱导耐受的细胞因子，干扰素-γ的这种出人意料的作用。 2.外周产生的调节性T细胞(Treg)的诱导和功能。使用一个模型 系统抗原识别后效应T细胞和Treg的顺序发育 研究将确定这两个细胞群体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F1移植物抗宿主反应的模型 将用于检测在多克隆T细胞情况下效应性和调节性T细胞的发育 反应性。 因此，本项目使用一套明确的实验系统和各种精确的分析方法来 研究外周T细胞耐受的基本机制及其诱导和维持 外部信号的调节。该项目与该项目之间有许多密切互动 CTLA-4和Treg的研究、信号转导途径、中央和中枢神经的相互作用 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，诱导耐受性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.