The function of PLZF in innate T cells

描述(申请人提供)：先天T细胞，如不变的自然杀伤T细胞(NKT细胞)，对感染具有极强的“第一反应”能力。与生俱来的T细胞的侵略性也使它们成为免疫治疗的诱人目标--几项临床试验正在进行中。像传统的T细胞一样，胸腺中的固有T细胞是由致力于胸腺中T细胞谱系的造血祖细胞发展而来的。对NKT细胞谱系的承诺直到T细胞发育的晚期才发生。我们最近发现，转录调控因子PLZF是控制NKT细胞效应器功能发育的因素。PLZF缺陷的NKT细胞不能获得固有T细胞所具有的效应功能，而异位表达PLZF的常规T细胞自发获得效应/记忆T细胞表型和功能。PLZF在人和鼠之间的氨基酸水平上是95%保守的，因此，几乎可以肯定在人身上的功能是相同的。事实上，人类NKT细胞表达高水平的PLZF。这一应用侧重于了解PLZF在NKT细胞中的功能以及该转录因子在先天T细胞发育和功能中所起的更普遍的作用。我们认为，PLZF是控制各种先天T细胞，而不仅仅是NKT细胞中效应功能的发展和维持的单一因素。我们的初步数据显示，PLZF的表达极大地影响了所有T淋巴细胞的功能。因此，研究T细胞表达PLZF、PLZF调控哪些效应功能、PLZF是如何启动的以及PLZF的调控机制，对于充分认识这种强大的转录因子对免疫的影响是至关重要的。我们在传统T细胞发育和NKT细胞发育方面的广泛知识，加上一系列新的试剂和实验系统，使我们处于一个极好的位置来扩展我们对这一关键转录因子的知识。 与公共卫生相关：先天T细胞，如不变的自然杀伤T细胞(iNKT细胞)，对感染具有极强的“第一反应”能力。与生俱来的T细胞的侵略性也使它们成为免疫治疗的诱人目标--几项临床试验正在进行中。我们最近发现，转录调控因子PLZF是控制iNKT细胞效应器功能发展的单一因素。在这项提案中，我们将确定PLZF的表达如何帮助控制免疫反应。

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.