Role of NF-κB c-Rel in regulating Natural Killer cell anti-tumor functions

项目摘要/摘要 免疫系统作为宿主防御机制，抵御入侵的病原体和 通过错综复杂的信号分子和特殊细胞网络转化细胞。 自然杀伤(NK)细胞是一种细胞毒性淋巴细胞，可以杀死感染病毒的细胞和癌细胞。他们 是肿瘤免疫监测不可或缺的组成部分。然而，自然杀伤细胞来自 癌症患者会出现功能障碍1-10。寻找调节NK细胞细胞毒作用的关键因素 功能对于理解导致NK细胞功能障碍的机制改变至关重要。 癌症。各种研究表明，NK细胞的细胞毒作用可由多种细胞因子介导，包括：IL-1、IL-2、IL-6、IL-6。 2、GM-csf、IL-15、IL-21、转化生长因子-β11-20，均受核因子-κB c-Rel21-23调控。核因子-κB-c- REL是一种转录因子，在髓系和淋巴细胞系中有成分表达24。 虽然c-Rel已被报道促进T细胞增殖和细胞因子的产生24-27，但 C-Rel在NK细胞中的作用尚不清楚。利用纯化的小鼠WT和c-WT的初步研究 Rel-/-NK细胞，表明c-Rel表达不足导致穿孔素表达减少和 小鼠NK细胞抗肿瘤功能受损。同样，c-rel的抑制作用与特定的小分子 分子抑制剂，导致穿孔素表达减少，并削弱其抗肿瘤细胞毒作用 人NK细胞。因此，我们试图确定c-rel在调节小鼠和人类中的作用。 NK细胞抗肿瘤细胞毒活性。第一个目标是确定c-rel在调节NK细胞中的作用。 细胞毒作用。第二个目标是研究c-rel调节NK细胞的机制。 细胞杀死肿瘤细胞的能力。完成这些目标将确定机制驱动的C-REL NK细胞细胞毒功能的调节。

Project Summary/Abstract The immune system serves as a host-defense mechanism against invading pathogens and transformed cells through an intricate network of signaling molecules and specialized cells. Natural Killer (NK) cells are cytotoxic lymphocytes that kill virus-infected and cancer cells. They are an integral component of tumor-immune surveillance. However, Natural Killer cells from cancer patients are rendered dysfunctional1-10. Finding key factors that regulate NK cell cytotoxic function is vital to understand the mechanistic alterations leading into NK cell dysfunction in cancer. Various studies show that NK cell cytotoxicity can be mediated by cytokines including: IL- 2, GM-CSF, IL-15, IL-21, and TGF-β11-20, all of which are regulated by NF-κB c-Rel21-23. NF-κB c- Rel is a transcription factor that is constitutively expressed in myeloid and lymphocytic lineages24. Although c-Rel has been reported to promote T cell proliferation and cytokine production24-27, the role of c-Rel in NK cells remains unknown. Preliminary studies utilizing purified murine WT and c- Rel-/- NK cells, show that deficiency in c-Rel expression results in reduced perforin expression and impaired anti-tumor function in murine NK cells. Similarly, inhibition of c-Rel with specific small molecule inhibitor, lead to decreased perforin expression and impaired anti-tumor cytotoxicity of human NK cells. We therefore seek to define the role of c-Rel in regulating mouse and human NK cell anti-tumor cytotoxic activity. The first aim will define the role of c-Rel in regulating NK cell cytotoxic function. The second aim will investigate the mechanism by which c-Rel regulates NK cells ability to kill tumor cells. Completion of these aims will define the mechanism-driven c-Rel regulation of NK cell cytotoxic function.