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首页> 外文学位 >Epigenetic regulation of killer immunoglobulin-like receptor gene expression in developing human natural killer cells.
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Epigenetic regulation of killer immunoglobulin-like receptor gene expression in developing human natural killer cells.

机译：发育中的人类自然杀伤细胞中杀伤免疫球蛋白样受体基因表达的表观遗传调控。

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摘要

The immune system is our primary defense against infection and disease. Immune cells need to recognize and efficiently destroy invasive pathogens while, at the same time, exercising tolerance towards normal cells and tissues within the body. Because pathogenic organisms are constantly evolving to evade detection, the immune system must employ multiple recognition strategies to keep pace. Natural killer (NK) cells have evolved a self versus non-self recognition strategy known as "missing self" that is based upon the recognition of self major histocompatibility complex (MHC) molecules by stochastically expressed inhibitory receptors on the surface of NK cells. When MHC expression is downregulated by a virus or cellular transformation event, the dampening signals that balance against NK cell activation are lost due to a lack of inhibitory receptor engagement. This lack of inhibitory signaling, along with the engagement of activating receptors, leads to the elimination of the distressed cell through targeted NK cell-mediated cytotoxicity. The work presented in this manuscript focuses on the transcriptional regulation of a critically important family of human NK cell inhibitory receptors known as killer immunoglobulin-like receptors (KIR).;The KIR genes are present within the leukocyte receptor complex on chromosome 19 and are expressed in a variegated, clonally restricted pattern on fully differentiated NK cells. How this pattern of gene expression is regulated during NK cell development is not well understood despite the demonstrated clinical relevance of KIR during hematopoietic cell transplantation to treat patients with leukemia, the influence of the KIR repertoire on the progression of HIV to AIDS, and the importance of KIR during pregnancy. Progress in the elucidation of how KIR genes are regulated has been slow due to the complexity of the KIR locus and the lack of KIR genes in mice, which are much more amenable to genetic manipulation.;We have shown that the 5' upstream regulatory region of each KIR gene contains a previously uncharacterized distal promoter with a functional c-Myc binding site. Stimulation of primary peripheral blood NK cells with IL-15 induces c-Myc binding at the distal promoter, which acts to promote KIR transcription. We also found that the overexpression of c-Myc protein in the NK92 cell line, which lacks surface KIR due to dense methylation of CpG dinucleotides proximal to the transcriptional start site, causes de novo surface KIR expression. Taken together, these results suggest that IL-15 directly promotes KIR transcription by inducing the binding of c-Myc to the distal promoter. We hypothesize that the recruitment of c-Myc and the initiation of active transcription from the distal promoter may also be key steps in the removal of repressive epigenetic marks within KIR promoters during human NK cell development to allow for stable gene expression.;In addition to identifying a novel distal promoter, our group has found that the conventional proximal KIR promoter exhibits bi-directional transcriptional activity, meaning that transcription can initiate in either the sense or antisense orientation. We observed a strong inverse correlation between the expression of KIR antisense transcripts and receptor expression on the cell surface, leading to the hypothesis that antisense transcripts directly participate in RNA-mediated transcriptional repression of individual KIR genes. We found that over-expressing full-length antisense transcripts during NK cell development led to an approximately 70% reduction in KIR expression compared to controls. Furthermore, we determined that full-length antisense transcripts are processed into a 28 base RNA with biochemical properties similar to those attributed to members of the PIWI family of small RNAs. We also demonstrate that the 28 base sequence is necessary for antisense transcript-mediated repression of KIR gene expression. This work establishes a direct association between KIR antisense transcription and the initiation of DNA methylation within the KIR promoter. Further elucidation of the mechanisms that regulate KIR expression during NK cell development may provide a basis for new strategies in the design of NK cell-based therapies.
机译：免疫系统是我们抵抗感染和疾病的主要防御手段。免疫细胞需要识别并有效破坏侵入性病原体，同时要对体内的正常细胞和组织产生耐受力。由于病原生物不断发展以逃避检测，因此免疫系统必须采用多种识别策略来跟上步伐。天然杀伤（NK）细胞已经进化出一种自我对非自我识别策略，称为“缺失自我”，该策略基于NK细胞表面上随机表达的抑制性受体对自身主要组织相容性复合体（MHC）分子的识别。当MHC表达被病毒或细胞转化事件下调时，由于缺乏抑制性受体的参与，失去了与NK细胞活化平衡的衰减信号。抑制信号的缺乏以及活化受体的参与导致通过靶向的NK细胞介导的细胞毒性消除了不良细胞。该手稿中的工作集中在人类NK细胞抑制受体的一个至关重要的家族的转录调控上，该受体被称为杀伤性免疫球蛋白样受体（KIR）.KIR基因存在于19号染色体上的白细胞受体复合物中并被表达。在完全分化的NK细胞上以杂色，无性系限制模式出现。尽管已证实在造血细胞移植过程中KIR在治疗白血病患者中的临床相关性，KIR谱表对HIV演变为AIDS的影响以及重要性，但尚未充分了解在NK细胞发育过程中如何调节这种基因表达模式。在怀孕期间的KIR。由于KIR基因座的复杂性和小鼠中KIR基因的缺乏，阐明KIR基因的调控方法的进展很慢，这更适合遗传操作。;我们已经表明5'上游调控区每个KIR基因中的一个含有一个先前未鉴定的带有功能性c-Myc结合位点的远端启动子。用IL-15刺激原代外周血NK细胞可在远端启动子处诱导c-Myc结合，从而促进KIR转录。我们还发现NK92细胞系中c-Myc蛋白的过表达（由于表面CIR转录起始位点附近的CpG二核苷酸的密集甲基化而缺乏表面KIR）导致从头开始表面KIR表达。综上所述，这些结果表明IL-15通过诱导c-Myc与远端启动子结合而直接促进KIR转录。我们假设c-Myc的募集和从远端启动子的主动转录的启动可能也是在人类NK细胞发育过程中去除KIR启动子内抑制性表观遗传标记以实现稳定基因表达的关键步骤。为了确定新的远端启动子，我们的小组发现常规的近端KIR启动子具有双向转录活性，这意味着转录可以以有义或反义方向启动。我们观察到KIR反义转录物的表达与细胞表面受体表达之间的强烈反相关，从而导致一个假设，即反义转录物直接参与单个KIR基因的RNA介导的转录抑制。我们发现，与对照组相比，NK细胞发育过程中过度表达的全长反义转录物导致KIR表达降低约70％。此外，我们确定将全长反义转录物加工成28个碱基的RNA，其生化特性与归因于小分子PIWI家族的成员相似。我们还证明了28个碱基的序列是反义转录介导的KIR基因表达抑制所必需的。这项工作建立了KIR反义转录与KIR启动子内DNA甲基化起始之间的直接联系。在NK细胞发育过程中调节KIR表达的机制的进一步阐明可能为基于NK细胞的疗法设计中的新策略提供基础。

著录项

  • 作者

    Cichocki, Frank M.;

  • 作者单位

    University of Minnesota.;

  • 授予单位 University of Minnesota.;
  • 学科 Health Sciences Immunology.
  • 学位 Ph.D.
  • 年度 2010
  • 页码 104 p.
  • 总页数 104
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

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