Regulation of humoral immunity by NKT cells

描述（由申请人提供）：疫苗接种或自然感染诱导的体液免疫的一个标志是它的寿命。然而，我们在适当编程B细胞反应的能力方面存在根本性的差距，这阻碍了针对包括艰难梭菌相关疾病在内的几种病原体的有效疫苗的开发。持久的抗体介导的对病原体的保护是由记忆B细胞赋予的，它可以对新抗原暴露做出快速反应，以及驻留在骨髓中并分泌特异性抗体的长寿浆细胞。NKT细胞为B细胞提供帮助，驱动记忆B细胞和浆细胞的分化和存活，从而增强对毒素、细菌和病毒的保护性抗体反应。然而，NKT细胞增强体液免疫的机制尚不清楚。我们的最新数据表明，不同的NKT功能亚群对记忆B细胞和浆细胞分化有不同的影响。我们的长期目标是系统地了解NKT细胞调节长期体液免疫的机制，并利用这些知识推动新疫苗的开发。该应用程序的总体目标是了解不同器官中NKT细胞的不同功能亚群如何对艰难梭菌毒素特异性抗体的产生和记忆B细胞和长寿浆细胞的分化产生不同的影响。因此，我们将验证次级淋巴器官、肝脏和骨髓中NKT细胞的特殊功能亚群对抗体产生、记忆B细胞诱导和长寿浆细胞持久性的差异调节的假设。为了做到这一点，我们将追求三个具体目标：具体目标1我们将确定NKT细胞诱导B细胞记忆的机制。特异性目标2我们将确定NKT细胞提高浆细胞存活的机制。特异性目标3，我们将鉴定增强抗体产生的NKT细胞的功能亚群。该方法是创新的，因为它应用了新的概念，即不同的NKT功能亚群对体液免疫的不同方面有不同的影响，因为它采用了新的工具来测量NKT驱动的记忆B细胞反应。这项研究具有重要意义，因为它有望扩大我们对NKT细胞如何控制体液免疫的方向、大小和持续时间的理解。在此过程中，我们将为利用NKT介导的体液免疫的新疫苗和/或改进疫苗提供基础，并以适当指导应答B细胞命运的方式这样做。

DESCRIPTION (provided by applicant): A hallmark of vaccination- or natural infection-induced humoral immunity is its longevity. However, there are fundamental gaps in our ability to appropriately program B cell responses, and this has hampered the development of efficacious vaccines for several pathogens including Clostridium difficile-associated disease. Persistent antibody mediated protection against pathogens is conferred by memory B cells that can respond rapidly to new antigen exposure as well as long-lived plasma cells that reside in the bone marrow and secrete specific antibody. NKT cells provide help to B cells, driving memory B cell and plasma cell differentiation and survival and thus enhance protective antibody responses against toxins, bacteria, and viruses. However, the mechanisms by which NKT cells enhance humoral immunity are poorly understood. Our newest data show that distinct NKT functional subsets exert diverse effects on memory B cell and plasma cell differentiation. Our long-term goal is to systematically develop an understanding of the mechanisms by which NKT cells regulate long-lived humoral immunity and use that knowledge to drive the development of new vaccines. The overall objective of this application is to understand how distinct functional subsets of NKT cells in different organs exert diverse effects on the production of C. difficile toxin-specific antibody and differentiation of memory B cells and long-lived plasma cells. We will therefore test the hypothesis that specialized functional subsets of NKT cells in secondary lymphoid organs, liver, and bone marrow differentially regulate antibody production, memory B cell induction and persistence of long-lived plasma cells. To do this, we will pursue three specific aims: Specific Aim 1 we will identify the mechanism by which NKT cells induce B cell memory. Specific Aim 2 we will identify the mechanism by which NKT cells enhance survival of plasma cells. Specific Aim 3 we will identify functional subsets of NKT cells that enhance antibody production. The approach is innovative because it applies the new concept that different NKT functional subsets have distinct effects on different aspects of humoral immunity and because it employs novel tools to measure NKT-driven memory B cell responses. The proposed research is significant because it is expected to expand our understanding of how NKT cells govern the direction, magnitude, and duration of humoral immunity. In doing so, we will provide the basis for new and/or improved vaccines that harness NKT- mediated humoral immunity, and do so in a manner that appropriately directs the fate of responding B cells.