The function of PLZF in innate T cells

PLZF 在先天 T 细胞中的功能

• 批准号: 8724069
• 负责人: Derek B. Sant'Angelo
• 金额: $ 7.15万
• 依托单位: RBHS-ROBERT WOOD JOHNSON MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-01 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8724069
• 关键词: Acute Promyelocytic Leukemia; Affect; Amino Acids; Applications Grants; Biological Models; Breeding; CD4 Positive T Lymphocytes; Cell Lineage; Cells; Clinical Trials; Commit; Data; Development; Genetic; Hematopoietic; Human; Immune response; Immune system; Immunity; Immunotherapy; Infection; Knowledge; Maintenance; Molecular; Mus; Nature; Pathway interactions; Phenotype; Play; Positioning Attribute; Publishing; Reagent; Regulation; Role; Series; Signal Transduction; Stromal Cells; System; T memory cell; T-Cell Development; T-Lymphocyte; Thymocyte Selection; Thymus Gland; Transgenes; Transgenic Mice; Zinc Fingers; cell type; emergency service responder; killer T cell; man; novel; precursor cell; programs; thymocyte; transcription factor

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.

描述（由申请人提供）：先天性T细胞，如不变的自然杀伤T细胞（NKT细胞），是对感染极有效的“第一反应者”。先天性T细胞的攻击性也使它们成为免疫治疗的有吸引力的靶点-几项临床试验正在进行中。与常规T细胞一样，先天性T细胞在胸腺中从造血前体细胞发育，所述造血前体细胞在胸腺中定型为T细胞谱系。对NKT细胞谱系的定型直到T细胞发育后期才发生。我们最近发现，转录调节因子，PLZF，是控制NKT细胞效应功能的发展的因素。PLZF缺陷型NKT细胞不能获得归因于先天性T细胞的效应子功能，并且异位表达PLZF的常规T细胞自发获得效应子/记忆T细胞表型和功能。PLZF在小鼠和人之间的氨基酸水平上>95%保守，因此，几乎可以肯定在人中功能等同。事实上，人NKT细胞表达高水平的PLZF。本申请的重点是了解PLZF在NKT细胞中的功能，以及这种转录因子在先天性T细胞发育和功能中的更一般作用。我们认为PLZF是控制各种先天性T细胞中效应子功能的发展和维持的单一因子，而不仅仅是NKT细胞。我们的初步数据表明，所有T淋巴细胞的功能显着影响PLZF的表达。因此，研究了解什么T细胞表达PLZF，PLZF控制什么效应子功能，PLZF表达如何启动以及PLZF调节机制对于充分理解这种强大的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，使我们能够扩展对这一关键转录因子的了解。