The function of PLZF in innate T cells

描述（由申请人提供）：先天T细胞，如不变的自然杀伤T细胞（NKT细胞），是对感染极其有效的“第一反应者”。先天T细胞的侵袭性也使它们成为免疫治疗的有吸引力的目标——一些临床试验正在进行中。与传统T细胞一样，先天T细胞在胸腺中由造血前体细胞发育而来，这些造血前体细胞与胸腺中的T细胞谱系结合。对NKT细胞谱系的承诺直到T细胞发育晚期才发生。我们最近发现，转录调节因子PLZF是控制NKT细胞效应功能发展的因子。PLZF缺陷的NKT细胞无法获得固有T细胞的效应功能，而异位表达PLZF的常规T细胞则自发获得效应/记忆T细胞表型和功能。PLZF在氨基酸水平上在小鼠和人类之间保守95%，因此几乎可以肯定在人类中功能相同。事实上，人类NKT细胞表达高水平的PLZF。这项应用的重点是了解PLZF在NKT细胞中的功能，以及这种转录因子在先天T细胞发育和功能中发挥的更普遍的作用。我们认为PLZF是控制多种先天T细胞中效应功能发育和维持的单一因素；不仅仅是NKT细胞。我们的初步数据表明，所有T淋巴细胞的功能都受到PLZF表达的显著影响。因此，了解哪些T细胞表达PLZF、PLZF控制哪些效应功能、如何启动PLZF表达以及PLZF调控机制对于充分认识这一强大转录因子对免疫的影响至关重要。我们在传统T细胞发育和NKT细胞发育方面的广泛知识与一系列新型试剂和实验系统相结合，为扩展我们对这一关键转录因子的知识奠定了良好的基础。

DESCRIPTION (provided by applicant): Innate T cells, such as the invariant natural killer T cells (NKT cells), are extremely potent "first responders" to infection. The aggressive nature of innate T cells has also made them attractive targets for immunotherapy - several clinical trials are in progress. Like conventional T cells, innate T cells develop in the thymus from hematopoietic precursor cells that commit to the T cell lineage in the thymus. Commitment to the NKT cell lineage does not occur until late in T cell development. We have recently discovered that the transcriptional regulator, PLZF, is the factor that controls the development of NKT cell effector functions. PLZF deficient NKT cells fail to acquire the effector functions ascribed to innate T cells and conventional T cells ectopically expressing PLZF spontaneously acquire effector/memory T cell phenotypes and functions. PLZF is >95% conserved at the amino acid level between mouse and man and, therefore, is nearly certainly functionally equivalent in people. Indeed, human NKT cells express high levels of PLZF. This application is focused on understanding the function of PLZF in NKT cells and the more general role this transcription factor plays in innate T cell development and function. We propose that PLZF is the single factor that controls the development and maintenance of effector functions in a variety of innate T cells; not only NKT cells. Our preliminary data show that the functions of all T lymphocytes are dramatically affected by the expression of PLZF. Therefore, studies to understand what T cells express PLZF, what effector functions are controlled by PLZF, how PLZF expression is initiated and the mechanism of PLZF regulation are critical for the full appreciation of the impact that this powerful transcription factor has on immunity. Our extensive knowledge of both conventional T cell development and NKT cell development in combination with a series of novel reagents and experimental systems puts in an excellent position to expand upon our knowledge of this critical transcription factor. PUBLIC HEALTH RELEVANCE: Innate T cells, such as the invariant natural killer T cells (iNKT cells), are extremely potent "first responders" to infection. The aggressive nature of innate T cells has also made them attractive targets for immunotherapy - several clinical trials are in progress. We have recently discovered that the transcriptional regulator, PLZF, is the single factor that controls the development of iNKT cell effector functions. In this proposal we will determine how PLZF expression helps to control the immune response.