Mechanisms and consequences of iNKT cell anergy

描述（由申请方提供）：不变自然杀伤T（iNKT）细胞是T淋巴细胞的一个亚群，可识别由MHC I类相关蛋白CD 1d呈递的糖脂抗原。新出现的证据表明，iNKT细胞在免疫系统中起着调节作用。该提案的长期目标是更好地了解小鼠对iNKT细胞的各种刺激物的体内免疫应答，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，原型iNKT细胞抗原α-半乳糖神经酰胺（GalCer）可以预防1型糖尿病，多发性硬化症和狼疮实验模型中的疾病。尽管GalCer治疗对各种疾病过程有影响，但我们对iNKT细胞本身对糖脂抗原的反应的理解是有限的。我们实验室最近的研究表明，iNKT细胞对GalCer活化的反应的特征在于表面受体下调、扩增、细胞因子产生、与其他细胞的串扰、稳态收缩和无反应性表型的获得。在这些初步研究结果的指导下，我们提出的研究将测试以下总体假设：iNKT细胞的糖脂激活启动了无反应性诱导程序，对随后的iNKT细胞控制的免疫应答具有长期影响。我们将在三个综合具体目标中检验这一假设：目标1将确定对诱导和维持长期iNKT细胞无反应性至关重要的细胞相互作用，目标2将研究诱导和维持iNKT细胞无反应性所涉及的生化机制，目标3将评估iNKT细胞对后续iNKT细胞控制的免疫应答的无应答性的长期影响。完成本提案中描述的工作将为基本iNKT细胞生物学、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性提供新的见解。这些拟议的研究将为建立安全有效的基于iNKT细胞的疫苗和疗法奠定知识基础。与公共卫生的相关性：本申请中提出的研究将显著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。

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.