The Role for NKAP in iNKT cell development

NKAP 在 iNKT 细胞发育中的作用

• 批准号: 8087797
• 负责人: Virginia Smith Shapiro
• 金额: $ 23.66万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-15 至 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8087797
• 关键词: Alphaproteobacteria; Antigens; Autoimmune Diseases; Autoimmunity; Bacteria; Borrelia; CD8B1 gene; Cell physiology; Cells; Clinical Trials; Defect; Development; Diabetes Mellitus; Failure; Family; Gene Expression; Generations; Genetic; Genetic Recombination; Glycolipids; Hour; Immune response; Lyme Disease; Lymphocyte; Malignant Neoplasms; Modeling; Molecular; Mus; Names; Pathway interactions; Phase; Role; SLAM protein; Staging; T-Cell Development; T-Cell Receptor; T-Lymphocyte; Thymocyte Development; Transcription Repressor/Corepressor; Transgenes; base; chemokine; cytokine; fighting; graft vs host disease; notch protein; novel; pathogen; receptor; thymocyte; tumor

DESCRIPTION (provided by applicant): NKT cells are a unique innate lineage of lymphocytes which express a¿ T cell receptors of limited diversity and recognize glycolipid antigens presented on MHC-like CD1d molecules. A subset of NKT cells express an invariant TCR1 chain, Va14-Ja18 in mice, and are thus named iNKT ("invariant NKT cells"). NKT cells respond quickly to antigenic stimulation, producing significant quantities of cytokines and chemokines within minutes or hours, which regulate the immune response. In addition to having an important role in the clearance of a subset of alpha-proteobacteria, iNKT cells have also been shown to regulate tumor surveillance and tumor rejection, autoimmune diseases, and graft versus host disease (GVHD). Because of their anti-tumor effects, clinical trials are underway to mobilize and activate iNKT cells in fighting cancer. iNKT cells develop via a distinct pathway from 'conventional' a¿ T cells, although they share CD4+CD8+ (DP) thymocytes as a common precursor. We have recently cloned a novel transcriptional repressor, NKAP, from a genetic complementation screen. Previously, we demonstrated that NKAP is required early in T cell development, as conditional deletion of NKAP, using an Lck-cre transgene, results in an early block in a¿ T cell development but leaves ?d T cell development unaffected. To understand the function of NKAP later in a¿ T cell development, we generated CD4-cre NKAP cKO mice, which delete NKAP efficiently at the DP stage of thymocyte development. Loss of NKAP expression in DP T cells leads to a complete abrogation of iNKT cell development, while conventional a¿ T cell development is unaffected. This defect in iNKT cell generation is not due to lack of CD1d expression in DP T cells, nor in their expression of two Slam family receptors that are critical to iNKT cell development, Slamf1 (also known as CD150) and Slamf6 (also known as Ly108). In this proposal, we will define the molecular cause(s) for the failure in the development of iNKT cells in the absence of NKAP. PUBLIC HEALTH RELEVANCE: Invariant NKT cells (iNKT) are critical to generating an immune response against pathogens, including Borrelia (the genus of bacteria responsible for Lyme disease). In addition, activation of iNKT cells can ameliorate autoimmunity in the NOD model of diabetes. Phase I/II clinical trials in which iNKT cells are activated to harness anti-tumor activity have been initiated. This proposal will focus on understanding the role of NKAP in the generation and activation of iNKT cells.

描述（由申请人提供）：NKT细胞是一种独特的先天淋巴细胞谱系，表达有限多样性的T细胞受体，并识别在mhc样CD1d分子上呈现的糖脂抗原。在小鼠中，NKT细胞的一个子集表达一个不变的TCR1链，Va14-Ja18，因此被命名为iNKT（“不变NKT细胞”）。NKT细胞对抗原刺激反应迅速，在几分钟或几小时内产生大量的细胞因子和趋化因子，从而调节免疫反应。除了在α -变形菌亚群的清除中发挥重要作用外，iNKT细胞还被证明可以调节肿瘤监测和肿瘤排斥反应、自身免疫性疾病和移植物抗宿主病（GVHD）。由于其抗肿瘤作用，临床试验正在进行动员和激活iNKT细胞来对抗癌症。iNKT细胞通过与“传统”T细胞不同的途径发育，尽管它们共享CD4+CD8+ (DP)胸腺细胞作为共同的前体。我们最近克隆了一个新的转录抑制因子，NKAP，从遗传互补筛选。在此之前，我们证明了NKAP在T细胞发育的早期是必需的，因为使用Lck-cre转基因条件删除NKAP会导致T细胞发育的早期阻滞，但会留下？T细胞发育不受影响。为了了解NKAP在T细胞发育后期的功能，我们产生了CD4-cre的NKAP cKO小鼠，它们在胸腺细胞发育的DP阶段有效地删除了NKAP。DP T细胞中NKAP表达的缺失导致iNKT细胞发育完全中断，而传统的a¿T细胞发育不受影响。iNKT细胞生成中的这种缺陷不是由于DP T细胞中缺乏CD1d表达，也不是由于它们表达对iNKT细胞发育至关重要的两种Slam家族受体Slamf1（也称为CD150）和Slamf6（也称为Ly108）。在本提案中，我们将定义在缺乏NKAP的情况下iNKT细胞发育失败的分子原因。