T cell immunity and cytokine receptor signaling

活化的T细胞发育成武装效应细胞或最终持续存在的过程 因为长寿记忆细胞正变得更好地被理解。通过IL-1介导的信号转导 2R对这些过程有显著的贡献。IL-2促进最佳T效应反应和 对于广泛的效应细胞在体外的增殖和发育是必不可少的。此外，最近 数据表明，初级反应过程中的IL-2信号可能对记忆CD8 T至关重要 细胞在召回抗原挑战时进行增殖和调节效应器活性。不过， 调节效应器对记忆编程的分子机制和精确的 IL-2对这些过程的贡献在很大程度上仍未确定。在我们上一次的资助期间， 我们开发了一种培养系统，模拟效应和记忆T细胞的发育和 外周T细胞在IL-2R信号通路中选择性缺陷的独特小鼠模型 细胞。这些实验工具对于直接分析IL-2依赖是特别有用的 分子事件控制效应器和内存编程。利用这些，我们发现了一种 在IL-2抑制自身产生的新的自动调节环路中，这可能是一个重要的 效应器和/或内存生产的检查点。这一抑制途径依赖于 转录抑制因子Blimp-1因此，这项提案的主要目标是建立 IL-2信号调节效应器和存储单元编程的分子基础 确定Blimp-1依赖的活化T细胞调节的生物学相关性。这个 具体目标是：1)研究IL-2R？信号如何调节个体下游 活化的CD4和CD8T细胞的分子靶点；2)确定IL-2R的相关性 体内对名义抗原和感染性免疫反应发展过程中的信号转导 3)直接评价IL-2依赖的Blimp-1在T细胞免疫中的作用 回应。

The processes by which activated T cells develop into armed effector cells or ultimately persist as long-lived memory cells are becoming better understood. Signal transduction through the IL- 2R prominently contributes to these processes. IL-2 promotes optimal T effector responses and is essential for extensive effector cell proliferation and development in vitro. Furthermore, recent data suggest that IL-2 signaling during the primary response may be critical for memory CD8 T cells to proliferate and mediate effector activity upon a recall antigenic challenge. Nevertheless, the molecular mechanism that regulates effector versus memory programming and the precise contribution by IL-2 to these processes remains largely undefined. During our last grant period, we developed a culture system that models effector and memory T cell development and characterized unique mouse models with selective defects in IL-2R signaling by peripheral T cells. These experimental tools are especially useful for direct analysis of IL-2-dependent molecular events controlling effector and memory programming. Utilizing these, we uncovered a novel auto-regulatory loop in which IL-2 inhibits its own production that may be an important checkpoint for effector and/or memory production. This inhibitory pathway depends upon the transcriptional repressor Blimp-1.Thus, the major objectives for this proposal are to establish the molecular basis by which IL-2 signaling regulates effector and memory cell programming and to ascertain the biological relevance of Blimp-1-dependent regulation of activated T cells. The specific aims are: 1) To investigate how IL-2R¿ signaling regulates individual down-stream molecular targets in activated CD4 and CD8 T cells; 2) to determine the relevance of IL-2R
signaling during the development of immune responses in vivo to nominal antigen and infectious agents; and 3) to directly evaluate the function of IL-2-dependent Blimp-1 in T cell immune responses.