Control of cytokine production by human NK cells

 描述（由申请人提供）：我们的实验室表明，转录因子早幼粒细胞白血病锌指（PLZF，zbtb 16）对自然杀伤T细胞（NKT细胞）效应功能的发展至关重要。这种高度保守的蛋白质也在人和大鼠NKT细胞中表达。表达PLZF的淋巴细胞与不表达PLZF的淋巴细胞相比具有完全不同的特征和效应子功能;细胞可以通过这种转录因子的表达转化为不同的谱系。与小鼠和大鼠相反，我们已经表明PLZF由所有人NK细胞表达。此外，我们已经表明，NK细胞从唯一已知的人在世界上有一个双等位基因的功能丧失PLZF具有改变的表型和功能。我们提出一种新的转录因子网络控制人类NK细胞反应的自我调节。该网络将通过使用原代人NK细胞和使用PLZF缺陷型NK细胞来研究，我们将从我们从PLZF缺陷型人中制备的诱导多能干细胞中分化出来。这些研究具有重要意义，因为尽管NK细胞疗法在治疗癌症等疾病方面前景广阔，但临床成功率有限。了解激活检查点将为增强治疗性NK细胞活性提供靶点。

 DESCRIPTION (provided by applicant): Our lab showed that the transcription factor promyelocytic leukemia zinc finger (PLZF, zbtb16) is essential for the development of the effector functions of natural killer T cells (NKT cells). This highly conserved protein is also expressed in human and rat NKT cells. Lymphocytes that express PLZF take on wholly different characteristics and effector functions than non-PLZF expressing lymphocytes; the cells are arguably transformed into a distinct lineage by the expression of this transcription factor. In contrast to mice and rats, we have shown that PLZF is expressed by all human NK cells. Furthermore, we have shown that NK cells from the only known person in the world to have a biallelic loss of function of PLZF have both an altered phenotype and function. We propose that a novel transcription factor network controls the self-regulation of NK cell responses in humans. This network will be studied by the use of primary human NK cells and by the use of PLZF deficient NK cells that we will differentiate from induced pluripotent stem cells that we made from the PLZF deficient person. These studies are of high significance because, although NK cell therapies hold great promise for the treatment of diseases such as cancer, clinical success has been limited. Understanding activation checkpoints will provide targets for enhancing therapeutic NK cell activity.