Growth Factor Signaling, Cell Division and T cell Anergy

T细胞无能是外周免疫耐受的一个重要机制，在自身免疫和移植的实验模型中控制免疫病理学的发展，很可能在人类临床器官移植的背景下进行操作。免疫上重要的共刺激受体CD28和CTLA-4主要通过影响T细胞生长因子的产生来调节无能的诱导。T细胞生长因子，如IL-2，是T细胞无能的有效抑制剂，同样对同种异体移植反应的结果产生强大的影响。尽管关于生长因子促进T细胞增殖和存活的途径有丰富的信息，但令人惊讶的是，关于T细胞生长因子如何对抗无能的诱导，以及IL-2和IL-15等生长因子如何在同种异体免疫反应中促进移植物排斥反应，人们知之甚少。这项建议的目的是进一步剖析CD28、CTLA-4和IL-2信号如何控制无能和效应器分化之间的决定，以及这些信号通过调节细胞分裂在多大程度上发挥作用。本文所描述的实验将使我们能够确定细胞周期进展对于IL-2介导的无能回避是必要的还是充分的，并确定哪些IL-2受体偶联的信号通路对无能避免和效应器T细胞分化有特定的贡献。我们将解决的具体问题是：1)耐受刺激是否通过抑制细胞周期进程在原代T细胞中诱导无能？2)IL-2受体偶联信号转导的哪些方面对原代T细胞无能的避免和效应功能的发展至关重要？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同种免疫反应中对体内T细胞效应功能做出贡献？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细胞无能的诱导和耐受的发展，可能会导致更具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.