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 随着人们对长寿记忆细胞的了解越来越多通过IL-1的信号转导 2 R对这些过程做出了突出贡献。IL-2促进最佳T效应子应答， 是体外广泛效应细胞增殖和发育所必需的。此外，最近 数据表明，在初级应答期间IL-2信号传导可能对记忆性CD 8 T细胞至关重要， 细胞增殖并介导回忆抗原激发后的效应子活性。然而，尽管如此， 调节效应器与记忆编程的分子机制以及精确的 IL-2对这些过程的贡献在很大程度上仍不明确。在我们上一次资助期间， 我们开发了一种模拟效应和记忆T细胞发育的培养系统， 通过外周T细胞介导的IL-2 R信号传导选择性缺陷表征独特的小鼠模型 细胞这些实验工具对于直接分析IL-2依赖性 分子事件控制效应器和存储器编程。利用这些，我们发现了一个 一种新的自动调节环，其中IL-2抑制其自身的生产，这可能是一个重要的 用于效应器和/或存储器产生的检查点。这种抑制途径依赖于 因此，本提案的主要目标是建立转录抑制因子Blimp-1的基因组。 IL-2信号传导调节效应细胞和记忆细胞编程的分子基础， 确定Blimp-1依赖性调节活化T细胞的生物学相关性。的 具体目标是：1）研究IL-2 R信号如何调节个体下游 活化的CD 4和CD 8 T细胞中的分子靶点; 2）确定IL-2 R
在体内对标称抗原和感染性抗原的免疫应答的发展过程中， 3）直接评价IL-2依赖性Blimp-1在T细胞免疫中的功能 应答

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.