RAE-1 Family of Proteins in Innate and Adaptive Immunity

描述(申请人提供)：自然杀伤(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，它们与同种异体移植排斥反应有关，可能还与某些自身免疫性疾病有关。NK细胞上负责激活它们的受体直到现在才被认识到。其中一种受体NKG2D被认为与NK细胞杀死某些肿瘤和病毒感染细胞的能力有关。NKG2D表达于所有NK细胞、CDS+T细胞、Gammadelta-TCR+T细胞和部分活化的巨噬细胞。最近，我们和其他人克隆了一个小鼠基因家族，命名为RAE-1，编码与小鼠NKG2D高亲和力结合的MHC类I类蛋白。人类RAE-1基因(命名为ULBP或RAE-1-like基因)的同源基因已被鉴定，这些基因编码的蛋白质可被人类NKG2D受体识别。在人类中，NKG2D受体还识别MICA和MICB，这是由应激、转化和病毒感染诱导的多态MHC I类抗原。新的证据表明，RAE-1和MIC糖蛋白可能触发由NK细胞和Gammadelta-TCR+T细胞介导的先天免疫反应，并与CD8+细胞毒性T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，并确定它们在先天性和获得性免疫反应中的作用。该计划的具体目标是：1)确定RAE-1基因是否具有多态，分析其表达并确定它们是否引发同种异体反应；2)建立病毒感染过程中RAE-1分子诱导的相关性，确定人CMV UL 16蛋白和潜在的其他病毒蛋白如何干扰RAE-1，以及评估除巨细胞病毒外的病毒是否诱导RAE-1基因，以及3)评估在正常细胞中诱导RAE-1基因的机制。该项目的总体目标是了解RAE-1抗原家族在先天性和获得性免疫反应中的有益和潜在的不利作用。

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.