Mechanisms and consequences of iNKT cell anergy

描述(申请人提供)：不变自然杀伤T细胞(INKT)是识别由MHC类L相关蛋白CD1d呈递的糖脂抗原的T淋巴细胞的亚群。越来越多的证据表明，iNKT细胞在免疫系统中起着调节作用。这项建议的长期目标是更好地了解小鼠对各种iNKT细胞刺激物的体内免疫反应，并利用这些信息开发更好的人类疾病预防和治疗方法。我们实验室的研究表明，典型的iNKT细胞抗原，α-半乳糖基神经酰胺(GalCer)可以预防实验性1型糖尿病、多发性硬化症和狼疮的疾病。尽管GalCer治疗对多种疾病过程有影响，但我们对iNKT细胞本身对糖脂抗原的反应的了解有限。我们实验室最近的研究表明，iNKT细胞对GalCer激活的反应以表面受体下调、扩张、细胞因子产生、与其他细胞的串扰、内稳态收缩和获得无能表型为特征。在这些初步发现的指导下，我们拟议的研究将检验总体假设，即iNKT细胞的糖脂激活启动无能诱导程序，并对随后的iNKT细胞控制的免疫反应产生长期影响。我们将在三个综合的特定目标中检验这一假设：目标1将确定对诱导和维持长期iNKT细胞无能至关重要的细胞相互作用，目标2将研究诱导和维持iNKT细胞无能所涉及的生化机制，以及目标3将评估iNKT细胞无应答对下一代iNKT细胞控制的免疫反应的长期影响。这项建议中所描述的工作的完成将为iNKT细胞的基本生物学、iNKT细胞对糖脂抗原的反应以及iNKT细胞在健康和疾病期间的免疫调节活动提供新的见解。这些拟议的研究将为建立安全有效的iNKT细胞疫苗和疗法奠定知识基础。与公共卫生的相关性：本申请中建议的研究将大大有助于开发更好的感染、癌症和自身免疫(例如1型糖尿病、多发性硬化症和狼疮)、过敏性和炎症性(例如动脉粥样硬化)疾病的预防措施和治疗方法。

DESCRIPTION (provided by applicant): Invariant natural killer T (iNKT) cells are a subset of T lymphocytes that recognize glycolipid antigens presented by the MHC class l-related protein CD1d. Emerging evidence indicates that iNKT cells play a regulatory role in the immune system. The long-term goal of this proposal is to obtain a better understanding of the in vivo immune response of mice to various stimulators of iNKT cells and to utilize this information for the development of better prophylactic and therapeutic approaches of human disease. Studies from our laboratory have demonstrated that the prototypical iNKT cell antigen, alpha-galactosylceramide (GalCer) can prevent disease in experimental models of type 1 diabetes, multiple sclerosis and lupus. Despite the impact of GalCer treatment on a variety of disease processes, our understanding of the response of iNKT cells themselves to glycolipid antigens is limited. Recent studies from our laboratory have demonstrated that the response of iNKT cells to GalCer activation is characterized by surface receptor down-modulation, expansion, cytokine production, cross-talk with other cells, homeostatic contraction, and acquisition of an anergic phenotype. Guided by these preliminary findings, our proposed studies will test the overall hypothesis that glycolipid activation of iNKT cells initiates a program of anergy induction with long-term effects on subsequent iNKT cell-controlled immune responses. We will test this hypothesis in three integrated Specific Aims: Aim 1 will determine the cellular interactions that are critical for the induction and maintenance of long-term iNKT cell anergy, Aim 2 will investigate the biochemical mechanisms involved in the induction and maintenance of iNKT cell anergy, and Aim 3 will evaluate the long-term effects of iNKT cell unresponsiveness to the subsequent generation of iNKT cell-controlled immune responses. Completion of the work described in this proposal will provide novel insight into fundamental iNKT cell biology, the response of iNKT cells to glycolipid antigens, and the immunomodulatory activities of iNKT cells during health and disease. These proposed studies will build a foundation of knowledge on which safe and effective iNKT cell-based vaccines and therapies can be established. Relevance to Public Health: Studies proposed in this application will contribute significantly to the development of better preventive measures and therapies of infections, cancers, and autoimmune (e.g., type 1 diabetes, multiple sclerosis and lupus), allergic and inflammatory (e.g., atherosclerosis) diseases.