RAE-1 Family of Proteins in Innate and Adaptive Immunity

先天性和适应性免疫中的 RAE-1 蛋白家族

• 批准号: 6580157
• 负责人: LEWIS Lee LANIER
• 金额: $ 26.88万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-02-14 至 2008-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6580157
• 关键词: 3T3 cells; T cell receptor; antigen antibody reaction; bactericidal immunity; cellular immunity; clinical research; cytomegalovirus; flow cytometry; gene expression; gene induction /repression; genetically modified animals; green fluorescent proteins; human tissue; immunoregulation; laboratory mouse; natural killer cells; polymerase chain reaction; posttranslational modifications; receptor binding; receptor expression; virus protein

DESCRIPTION (provided by applicant): Natural killer (NK) cells participate in the innate immune response against pathogens and tumors. There is growing evidence that they are involved in allograft rejection and possibly in certain autoimmune diseases. The receptors on NK cells responsible for their activation are only now being appreciated. One of these receptors, NKG2D, has been implicated in the ability of NK cells to kill certain tumors and virus-infected cells. NKG2D is present on all NK cells, CDS+T cells, gammadelta-TcR + T cells and some activated macrophages. Recently, we and others cloned a family of mouse genes, designated RAE-1, encoding MHC class I-like proteins that bind with high affinity to mouse NKG2D. Human orthologs of the RAE-1 genes (designated as either ULBP or RAE-1-like genes) have been identified and the proteins encoded by these genes are recognized by the human NKG2D receptor. In humans, the NKG2D receptor also recognizes MICA and MICB, polymorphic MHC class I antigens that are induced by stress, transformation and viral infection. Emerging evidence suggests that the RAE-1 and MIC glycoproteins may serve to trigger the innate immune responses mediated by NK cells and gammadelta-TcR +T cells and function to co-stimulate antigen-specific responses by CD8 + cytotoxic T lymphocytes. We propose to investigate the RAE-1 family of genes and determine their role in innate and adaptive immune responses. The specific aims of this program are: 1) to determine whether the RAE-1 genes are polymorphic, analyze their expression and determine if they elicit allogeneic responses, 2) to establish the relevance of induction of the RAE-1 molecules during viral infection, to determine how the human CMV UL 16 protein and potentially other viral proteins interfere with RAE-1, and to evaluate whether viruses other than HCMV induce the RAE-1 genes, and 3) to evaluate the mechanisms responsible for the induction of the RAE-1 genes in normal cells. The overall objective of this project is to understand both the beneficial and potentially adverse functions of the RAE- 1 family of antigens in innate and adaptive immune responses.

描述（由申请人提供）：天然杀伤（NK）细胞参与对病原体和肿瘤的先天免疫反应。越来越多的证据表明，他们参与了同种异体移植的排斥和某些自身免疫性疾病。 NK细胞上负责其激活的受体直到现在才得以理解。这些受体之一NKG2D与NK细胞杀死某些肿瘤和病毒感染细胞的能力有关。 NKG2D都存在于所有NK细胞，CDS + T细胞，伽玛达尔塔TCR + T细胞和一些活化的巨噬细胞上。最近，我们和其他人克隆了一个指定为RAE-1的小鼠基因家族，编码与小鼠NKG2D高亲和力结合的MHC I类蛋白。已经鉴定出RAE-1基因的人类直系同源物（被指定为ULBP或RAE-1样基因），并且这些基因编码的蛋白质被人NKG2D受体识别。在人类中，NKG2D受体还识别由压力，转化和病毒感染诱导的多态性MHC I类抗原。新兴的证据表明，RAE-1和MIC糖蛋白可能有助于触发由NK细胞和Gammadelta-TCR + T细胞介导的先天免疫反应，并发挥通过CD8 +细胞毒性T淋巴细胞共同刺激抗原特异性反应。我们建议研究RAE-1基因家族，并确定它们在先天和适应性免疫反应中的作用。该程序的具体目的是：1）确定RAE-1基因是否是多态性的，分析其表达并确定它们是否引起同种响应，2）确定在病毒感染期间RAE-1分子诱导的相关性，确定人CMV UL 16蛋白和其他潜在的其他病毒蛋白如何干扰RAE-1，并评估HCMV以外的病毒是否诱导RAE-1基因以及3）评估负责RAE-的机制正常细胞中的1个基因。该项目的总体目的是了解先天和适应性免疫反应中Rae-1抗原家族的有益和潜在的不利功能。