Understanding the role of NF-kB in T-regulatory cell function

描述(申请人提供)：维持免疫平衡是生存的关键。除了提供病原体的有效清除外，精心平衡的免疫系统还必须通过防止对自身抗原的反应来限制自身免疫。最近对T调节(Treg)细胞的表征揭示了一条主要的调节途径，该途径用于防止免疫系统的不适当激活和维持体内平衡。T调节细胞在胸腺发育过程中产生，或在外周产生于暴露于特定细胞因子环境中的效应细胞(诱导T调节细胞或iTregs)。现在已经确定al Tregs的特征是转录因子Foxp3的表达，该转录因子协调有助于调节这些细胞的效应器功能的基因的产生。我们实验室最近的工作表明，蛋白激酶PDK1和转录因子NF-βB在Treg的发育和功能中起着关键作用。在广泛的初步研究中，我们现在已经证明，作为Treg功能的关键调节因子，核因子-βB明显参与了这一过程。然而，目前尚不清楚核因子？B是如何影响Treg功能的。在这项拨款申请中，我们将研究核因子-βB在Treg中的作用，而不仅仅是它调节Foxp3表达的作用。在第一个目的中，我们将通过诱导缺失核因子-β来确定核因子-β是否在FoxP3表达后的Treg分化中起作用。在第二个目标中，我们将描述Tregs中受核因子-βB调控的遗传程序。最后，在第三个目标中，我们将确定哪个信号通路负责激活Tregs中的核因子-βB，并探讨PKC？在这个过程中。

DESCRIPTION (provided by applicant): Maintenance of immune homeostasis is crucial for survival. In addition to providing effective clearance of pathogens, a carefully balanced immune system must also limit autoimmunity by preventing responses against self-antigens. The recent characterization of T-regulatory (Treg) cells has revealed a major regulatory pathway that is utilized to prevent inappropriate activation of the immune system and maintain homeostasis. T-regulatory cells arise either during thymic development (tTregs), or are generated in the periphery from effector cells exposed to particular cytokine milieu (induced T-regs or iTregs). It is now well established that al Tregs are characterized by the expression of the transcription factor Foxp3, which orchestrates the production of genes that help mediate the effector functions of these cells. Recent work in our laboratory has revealed that the protein kinase PDK1 and the transcription factor NF-?B play a critical role in Treg development and function. In extensive preliminary studies we have now demonstrated a clear involvement of NF-?B as a critical regulator of Treg function. However, exactly how NF-?B influences Treg function remains unclear. In this grant application we will investigate the role of NF-?B in Tregs beyond its role i regulating the expression of Foxp3. In the first aim we will determine whether NF-?B plays a role in Treg differentiation subsequent to FoxP3 expression by deleting NF-?B inducibly. In the second aim, we will characterize the genetic program in Tregs that is controlled by NF-?B. Finally, in the third aim, we will determine which signaling pathway is responsible for activating NF-?B in Tregs, and explore the role of PKC? in this process.