Functional analysis of NK cells and their potential to generate CTL responses

描述（由申请人提供）：NK细胞的功能分析及其产生CTL应答的潜力自然杀伤（NK）细胞检测并杀死病原体感染的宿主细胞，以及肿瘤细胞和组织同种异体移植物。然而，我们实验室最近的工作表明，它们还履行着另一项职责：在适应性免疫系统中建立NK细胞及其亲属之间的牢固联系。通过诱导表现出“缺失自我”的细胞凋亡，NK细胞促使强烈的CD 8 + T、CD 4 + T和B细胞应答。通过该途径的适应性免疫应答与用3-照射的细胞免疫后观察到的免疫应答相比被显著放大。虽然在先前的研究中，我们发现由3-照射的细胞诱导的适应性免疫应答不依赖于MyD 88/Trif信号传导而发生，但由NK细胞介导的细胞死亡诱导的应答-特别是在该途径中观察到的扩增-需要MyD 88/Trif依赖性组分。进一步的体外研究已经揭示，当暴露于通过Fas连接而凋亡的细胞时（但当暴露于3-照射的细胞时不），淋巴样DC释放增加水平的IL-12，这表明IL-12产生和随后的MyD 88途径信号传导可能是在该途径中观察到的扩增的原因.在当前的提议中，我们的目标是理解以下方面的潜在分子机制和生物学后果：（a）NK细胞特异性途径对产生稳健的CD 8 + T细胞应答的贡献;（B）由驱动CD 8 + T细胞应答的（NK细胞介导的）细胞死亡诱导的DC特异性活化途径。最后（c），我们的目标是了解由该途径驱动的CD 4 + T和B细胞应答的潜在分子机制和生物学后果。最终，NK细胞的这种新发现的功能可能对多种疾病具有重要意义，并且可以用于设计促进强细胞介导和体液免疫的有效疫苗。 公共卫生相关性：我们相信NK->DC->T/B细胞轴代表了产生强大的适应性免疫应答的基本途径，这可能为疫苗开发提供独特而强大的策略。此外，更好地了解这一途径可能是必不可少的，以提供深入了解的发展和/或控制各种疾病，包括病毒/细菌感染，自身免疫，和/或肿瘤性疾病。

DESCRIPTION (provided by applicant): Functional analysis of NK cells and their potential to generate CTL responses Natural Killer (NK) cells detect and kill pathogen-infected host cells, as well as neoplastic cells and tissue allografts. However, recent work in our laboratory suggests that they discharge another duty as well: one that establishes a strong tie between NK cells and their relatives in the adaptive immune system. By inducing apoptosis of cells that exhibit "missing self", NK cells prompt a strong CD8+ T, CD4+ T and B cell response. The adaptive immune responses via this pathway are significantly amplified compared to immune responses observed after immunization with 3-irradiated cells. While in previous studies, we found that the adaptive immune responses induced by 3-irradiated cells occurred independent of MyD88/Trif signaling, the responses induced by NK cell- mediated cell death-particularly the amplification observed in this pathway-requires a MyD88/Trif-dependent component. Further studies in vitro, have revealed that lymphoid DCs release increased levels of IL-12 when exposed to cells rendered apoptotic by Fas- ligation (but not when exposed to 3-irradiated cells), suggesting that IL-12 production and subsequent MyD88 pathway signaling could be responsible for the amplification observed in this pathway. In the current proposal, we aim to understand the underlying molecular mechanisms and biological consequences of: (a) the contributions of NK cell- specific pathways to the generation of robust CD8+ T cell responses; (b) the DC-specific activation pathways induced by (NK cell-mediated) cell death that drive CD8+ T cell responses. Finally (c), we aim to understand the underlying molecular mechanisms and biological consequences of CD4+ T and B cell responses driven by this pathway. Ultimately, this newly identified function of NK cells may have important implications for a wide variety of diseases, and may be exploited in the design of effective vaccines that promote strong cell-mediated and humoral immunity. PUBLIC HEALTH RELEVANCE: We believe that the NK->DC->T/B cell axis represents a fundamental pathway for the generation of robust adaptive immune responses that may provide a unique and powerful strategy for vaccine development. In addition, a better understanding of this pathway may be essential to provide insight into the development and/or control of a wide variety of diseases, including viral/bacterial infections, autoimmunity, and/or neoplastic diseases.