Control of cytokine production by human NK cells

 描述(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，zbtb16)对于自然杀伤T细胞(NKT细胞)的效应功能的发展是必不可少的。这种高度保守的蛋白也在人和大鼠的NKT细胞中表达。表达PLZF的淋巴细胞与不表达PLZF的淋巴细胞具有完全不同的特征和效应功能；可以说，细胞通过这种转录因子的表达而转变为不同的谱系。与小鼠和大鼠相比，我们已经证明PLZF在所有人类NK细胞中都有表达。此外，我们已经证明，来自世界上唯一已知的具有PLZF双等位基因功能丧失的人的NK细胞具有改变的表型和功能。我们认为，一个新的转录因子网络控制着人类NK细胞反应的自我调节。这个网络将通过使用原代人类NK细胞和使用PLZF缺陷的NK细胞来研究，我们将从PLZF缺陷者获得的诱导多能干细胞中分化出来。这些研究具有很高的意义，因为尽管NK细胞疗法在治疗癌症等疾病方面前景光明，但临床成功有限。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.