Identification of Novel Immune Cell- the NKDC

新型免疫细胞-NKDC的鉴定

• 批准号: 7540963
• 负责人: DREW M. PARDOLL
• 金额: $ 39.05万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-01-01 至 2010-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7540963
• 关键词: Antigens; Bacteria; Blood; Cell surface; Cells; Cellular Stress; Communication; Cross Presentation; Dendritic Cells; Development; Developmental Biology; Family; Family member; Genes; Geography; Grant; Granzyme; Hybrid Cells; Immune; Immune response; Immune system; Immunity; In Vitro; Infection; Interferon Type I; KLRA1 gene; Kinetics; Knockout Mice; Ligands; Link; Lymphoid; MHC Class II Genes; Malignant Neoplasms; Mediating; Mus; Myelogenous; Natural Immunity; Natural Killer Cells; Oligonucleotides; Pathway interactions; Process; Relative (related person); Role; Surface; T-Lymphocyte; TLR9 gene; Testing; Toll-like receptors; Transgenic Organisms; Up-Regulation; Upper arm; Virus; base; cell type; cytokine; in vivo; killings; lymph nodes; neoplastic cell; novel; progenitor; receptor; response; tumor

The innate and adaptive immune systems represent our two arms of defense against infection and cancer. Natural killer (NK) cells are a central component of innate immunity, recognizing infected cells, stressed cells and tumor cells via specific nonpolymorphic receptors. As the critical presenters of antigen to naive T cells, dendritic cells (DCs) are the critical initiators of adaptive immunity. Coordination of immune responses requires efficient communication between innate and adaptive immunity. Recently, we discovered a unique hybrid cell type that expresses both NK molecules (activating and inhibitory) and DC molecules, termed NKDC. Murine NKDCs are related to, but distinct from classic plasmacytoid DC (PDCs). Upon activation with CpG oligonucleotide ligands for toll-like receptor (TLR)-9, NKDC become transiently activated to kill target cells. The killing is, at least in part, NKG2D-dependent. Their NK activity subsequently diminishes associated with loss of NKG2D and its adaptor, DAP-12. As NK activity is lost, DC-like antigen presenting activity is gained, associated with upregulation of surface MHC class II and costimulatory molecules. In vivo, splenic NKDCs preferentially display NK activity while lymph node NKDCs preferentially display ARC activity. By virtue of their capacity to mediate natural killing activity, followed by antigen presenting activity, NKDC may represent a direct link between innate and adaptive immunity. We propose to characterize the development and functions of this cell type in detail. The following specific aims will be pursued. Specific Aim #1: Define the developmental biology of NKDC relative to NK cells and classic DC.Specific Aim #2: Define the activation, recognition and effector molecules involved in NKDC killing. Specific Aim #3: Define the capacity of NKDC to process and present antigens to T cells. Specific Aim #4: Define the role of NKDC in response to tumors.

先天和适应性免疫系统代表了我们针对感染和癌症的防御两个部门。 天然杀手（NK）细胞是先天免疫的核心组成部分，识别受感染的细胞，应力细胞 和肿瘤细胞通过特定的非晶型受体。作为对天真T细胞的抗原的关键演示者， 树突状细胞（DC）是适应性免疫的关键启动者。免疫反应的协调 需要先天和适应性免疫之间有效的沟通。最近，我们发现了一个独特的 表达NK分子（激活和抑制性）和DC分子的杂化细胞类型，称为 NKDC。鼠NKDC与经典的浆细胞样DC（PDC）有关。激活后 CpG寡核苷酸配体，用于收费类受体（TLR）-9，NKDC瞬时激活以杀死靶标 细胞。杀戮至少部分依赖于NKG2D。他们的NK活动随后减少 与NKG2D及其适配器DAP-12的丢失有关。随着NK活性丢失，DC样抗原呈现 获得活性，与表面MHC II类和共刺激分子的上调有关。体内， 脾脏NKDC优先显示NK活性，而淋巴结NKDC则优先显示ARC活性。 由于它们有能力调节自然杀戮活动，然后进行抗原表现活动，NKDC 可以代表先天和适应性免疫之间的直接联系。我们建议表征 该单元格的开发和功能详细介绍。将追求以下特定目标。具体目标 ＃1：定义NKDC相对于NK细胞和经典DC的发育生物学。特定目标＃2：定义 NKDC杀死涉及的激活，识别和效应分子。特定目的＃3：定义 NKDC处理和将抗原呈现与T细胞的能力。特定目标＃4：定义NKDC在 对肿瘤的反应。