Molecular Basis of iNKT Cell Ontogeny and Function

这个项目的长期目标是阐明不变自然T(INKT)的机制(S)。 细胞在健康和疾病中发挥作用。INKT细胞是重要的免疫调节先天淋巴细胞。他们 介导CDID限制性糖脂抗原α-半乳糖基神经酰胺(OtGalCer)的佐剂功能 对转移性肿瘤、某些感染和几种有效的体内免疫调节活性 自身免疫性疾病。体内激活的iNKT细胞快速而强大的细胞因子反应介导了它们的 免疫调节功能。个体发育过程中的指导过程决定了个体发育的效应器特性 淋巴细胞。我们理解iNKT细胞生物学的方法是阐明细胞间和 导致功能性iNKT细胞发育和分化的细胞内个体发生信号。我们 另一些人最近发现，经典的核因子kB(NF-kB)信号转导对于 INKT细胞的成熟和功能，而不是传统的T细胞个体发育。核因子-kB的这个功能是 主要依赖于NFkB1(细胞自主)，较小程度依赖于NFKB2，以及RelB(细胞外源性) 活动。因此，对激活核因子-kB的信号及其后果进行彻底的表征 INKT细胞的发育和分化是我们理解iNKT细胞生物学的基础。在这里，我们 将检验核心假设，即核因子-KB是一种特定于家族的调节因子，它处理和整合 多种细胞外信号精确调控功能性iNKT的发育和分化 细胞。为了验证这一中心假设，我们将寻求以下三个集成但独立的具体 目的：(A)明确iNKT细胞个体发育过程中TCR信号与核因子-kB活化的偶联机制(S)； (6)定义在发育过程中诱导iNKT细胞凋亡的信号；及(C)定义 核因子-kB调控iNKT细胞功能分化的机制(S)。在完成此操作后 我们的期望是确定核因子-kB调控个体发育的分子机制(S) 和功能性iNKT细胞的分化。这些发现将显著增强我们的根本 了解iNKT细胞生物学，将有助于更深入地了解iNKT的分子机制 细胞命运指定以及免疫系统内的分子和功能分化。 此外，这种知识可以导致治疗学的发展，这些疗法要么增强(佐剂) 影响、下调自身免疫)或抑制(脑型疟疾、呼吸道超敏)iNKT细胞功能。

The long-term goal of this project is to elucidate the mechanism(s) by which the invariant natural T (iNKT) cells function in health and disease. iNKT cells are important immunoregulatory innate lymphocytes. They mediate the adjuvant function of a-galactosylceramide (otGalCer), a CDId-restricted glycolipid antigen with potent in vivo immunomodulatory activities against metastatic tumours, certain infections and several autoimmune diseases. The rapid and robust cytokine response of in vivo activated iNKT cells mediates their immunoregulatory function. Instructional processes during ontogeny determine the effector properties of lymphocytes. Our approach to understanding iNKT cell biology has been to elucidate the intercellular and intracellular ontogenetic signals that lead to the development and differentiation of functional iNKT cells. We and others have recently discovered that classical nuclear factor KB (NF-kB) signalling is essential for the maturation and function of iNKT cells but not for conventional T cell ontogeny. This function of NF-kB is largely dependent on NFkB1 (cell autonomous), to a lesser extent on NFkB2, and RelB (cell extrinsic) activities. Therefore, a thorough characterisation of signals that activate NF-kB and its consequences during iNKT cell development and differentiation are essential to our understanding of iNKT cell biology. Here, we will test the central hypothesis that NF-KB is a lineage-specific regulator, which processes and integrates diverse extracellular signals that precisely regulate the development and differentiation of functional iNKT cells. To test this central hypothesis, we will pursue the following three integrated yet independent specific aims: (a) define the mechanism(s) that couples TCR signals to NF-kB activation during iNKT cell ontogeny; (6) define the signals that induce apoptosis in iNKT cells during development; and (c) define the mechanism(s) by which NF-kB regulates functional differentiation of iNKT cells. Upon completion of this project, our expectationis to define the molecular mechanism(s) by which NF-kB regulates the ontogeny and differentiation of functional iNKT cells. These findings will significantly enhance our fundamental understanding of iNKT cell biology and will lead to deeper insights into the molecular mechanisms underlying cell fate specification as well as molecular and functional differentiation within the immune system. Additionally, this knowledge can lead to the development of therapeutics that either enhance (adjuvant effect, downregulate autoimmunity) or suppress (cerebral malaria, airway hypersensitivity) iNKT cell function.