Growth Factor Signaling, Cell Division and T cell Anergy

T细胞能量是外周耐受的重要机制，在自身免疫和移植实验模型中控制免疫病理的发展，并且最有可能在人类临床器官移植的背景下起作用。免疫上重要的共刺激受体CD28和CTLA-4主要通过它们对T细胞生长因子产生的影响来调节能量的诱导。T细胞生长因子如IL-2是T细胞能量的有效抑制剂，同样对同种异体移植物反应的结果产生强大的影响。尽管关于生长因子促进T细胞增殖和存活的手段的信息丰富，但令人惊讶的是，关于T细胞生长因子如何反对诱导能量，以及IL-2和IL-15等生长因子如何在同种免疫反应中促进移植物排斥反应尚不清楚。本提案的目标是进一步剖析来自CD28， CTLA-4和IL-2的信号如何控制能量和效应分化之间的决定，以及这些信号通过调节细胞分裂在多大程度上起作用。本文所描述的实验将使我们能够确定细胞周期进程对于IL-2介导的能量回避是否是必要的或充分的，并确定哪些IL-2受体偶联的信号通路特别有助于能量回避和效应T细胞分化。我们将解决的具体问题是：1)耐受性刺激是否通过抑制细胞周期进展来诱导原代T细胞的能量？2)在原代T细胞中，IL-2受体偶联信号转导的哪些方面对能量规避和效应功能的发展是重要的？3)生长因子偶联信号通路和/或生长因子驱动的细胞分裂如何在体内同种免疫应答中促进T细胞效应功能？更彻底地了解CD28、CTLA-4和IL-2如何在临床移植环境中促进T细胞能量的诱导和耐受性的发展，可能会导致更特异性和更成功的治疗方法。

T cell anergy is an important mechanism of peripheral tolerance that controls the development of immunopathology in experimental models of autoimmunity and transplantation, and is most likely operative in the context of clinical organ transplantation in humans. The immunologically important costimulatory receptors CD28 and CTLA-4 regulate in the induction of anergy, primarily through their effects on the production of T cell growth factors. T cell growth factors such as IL-2 are potent inhibitors of T cell anergy, and likewise exert a powerful influence on the outcome of allograft responses. Despite the wealth of information concerning the means by which growth factors promote the proliferation and survival of T cells, surprisingly little is known about how T cell growth factors oppose the induction of anergy, and precisely how such growth factors as IL-2 and IL-15 promote graft rejection during an alloimmune response is unclear. The goal of this proposal is to further dissect how signals from CD28, CTLA-4 and IL-2 control the decision between anergy and effector differentiation, and to what extent these signals operate through the regulation of cell division. The experiments described here should allow us to determine whether cell cycle progression is necessary or sufficient for IL-2-mediated anergy avoidance, and to identify which IL-2 receptor-coupled signaling pathways specifically contribute to anergy avoidance and effector T cell differentiation. The specific questions we will address are: 1) Do toleragenic stimuli induce anergy in primary T cells by inhibiting cell cycle progression?, 2) Which aspects of IL-2 receptor-coupled signal transduction are important for anergy avoidance and development of effector function in primary T cells?, and 3) How do growth factor-coupled signaling pathways and/or growth factor-driven cell division contribute to T cell effector function in vivo during an alloimmune response? A more thorough understanding of how CD28, CTLA-4 and IL-2 contribute to the induction of T cell anergy and the development of tolerance in a clinical transplantation setting may lead to therapeutic approaches with greater specificity and success.