Immunobiology of NKT cell development and function

NKT 细胞发育和功能的免疫生物学

• 批准号: 8099344
• 负责人: Derek B. Sant'Angelo
• 金额: $ 22.09万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-12 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8099344
• 关键词: Autoimmune Diseases; Biology; Bone Marrow; Cancer Control; Cell physiology; Cell surface; Cells; Cellular biology; Commit; Data; Dependency; Development; Disease; Event; Family; Genes; Goals; Immune; Immune response; Immune system; Immunobiology; Inbred NOD Mice; Insulin-Dependent Diabetes Mellitus; Label; Learning; Ligands; Memory; Methods; Mus; Mutagenesis; Names; Natural Killer Cells; Nature; Organ Culture Techniques; Pathway interactions; Peripheral; Phenotype; Population; Property; Protein Kinase; Publishing; Regulation; Role; Series; Signal Transduction; System; T-Cell Development; T-Lymphocyte; TCR Activation; Techniques; Thymus Gland; Tissues; Transgenes; Travel; Work; chemical genetics; cytokine; design; fighting; gene therapy; killer T cell; member; mouse model; mutant; novel; precursor cell; progenitor; receptor; receptor expression; research study; retroviral-mediated; src-Family Kinases; thymocyte; tool; tumor

Invariant Natural Killer T cells (iNKT cells) are a rare but potent population of cells expressing features in common with both natural killer cells and T cells. These CD1d restricted cells have been shown to both positively and negatively modulate immune responses. Roles for iNKT cells range from fighting tumors to suppressing or curing various autoimmune diseases. The cells have numerous features that make them distinct from conventional T cells including their ability to release copious amounts of cytokines following primary activation, a highly restricted TCR repertoire, an activated or memory phenotype, expression of receptors typical of NK cells and unequal distribution in peripheral tissues, to name a few. Definitive proof that iNKT cells develop in the thymus has only recently been established. Little is known about the early development of these cells other than that it appears to be distinct from conventional T cell development. We propose to study several aspects of iNKT cell development ranging from an analysis of the TCR to a study of downstream signaling events in an effort to understand and potentially manipulate the development of these cells. We will first characterize properties of the unusual interaction of the iNKTCR with CD1d to learn how the biology of this remarkably strong TCR-ligand interaction helps define the function of iNKT cells. In Aim 2 we propose to analyze the critical and possibly unique function of the Src-family protein kinase, Fyn in iNKT cell development. The studies of Fyn will guide our search for a proposed second receptor that we believe is required for iNKT cell development. This work will also seek to modulate iNKT cell function by controlling aspects of their development in the thymus. Finally, in Aim 3, we will develop a method to tag developing iNKT cells very early in their development, perhaps prior to cell surface expression of the TCR. This approach will give us a tool to characterize and explore the mechanisms underlying iNKT cell development. Overall, these studies will contribute to our basic understanding of several critical aspects of iNKT cell biology. Understanding key aspects of iNKT cell development will eventually make it possible to alter the function of these cells using gene therapy approaches in an effort to control cancer and other diseases.

不变的自然杀伤T细胞（iNKT细胞）是一种罕见但有效的细胞群，表达免疫调节功能。 自然杀伤细胞和T细胞都有这些CD 1d限制性细胞已被证明是 积极和消极地调节免疫反应。iNKT细胞的作用范围从对抗肿瘤到 抑制或治愈各种自身免疫性疾病。这些细胞有很多特征 与常规T细胞不同，包括它们在免疫后释放大量细胞因子的能力。 初级活化，高度限制的TCR库，活化或记忆表型， NK细胞的典型受体和外周组织中的不均匀分布，仅举几例。 iNKT细胞在胸腺中发育的有力证据最近才得到证实。知之甚少 关于这些细胞的早期发育，除了它似乎与传统的T细胞不同之外， 发展我们建议研究iNKT细胞发育的几个方面，从分析 TCR是一项下游信号事件的研究，旨在理解和潜在地操纵TCR。 这些细胞的发育。我们将首先表征iNKTCR与 CD 1d来了解这种非常强的TCR-配体相互作用的生物学如何帮助定义 iNKT细胞。在目标2中，我们提出分析Src家族蛋白的关键和可能独特的功能 激酶、Fyn在iNKT细胞发育中的作用。对菲恩的研究将指导我们寻找第二个 我们认为这是iNKT细胞发育所必需的受体。这项工作还将寻求调节iNKT细胞 通过控制它们在胸腺中发育的各个方面来发挥作用。最后，在目标3中，我们将开发一种方法， 在iNKT细胞发育的非常早期，可能在细胞表面表达前， TCR。这种方法将为我们提供一个工具，以表征和探索的机制，iNKT细胞 发展 总之，这些研究将有助于我们对iNKT细胞的几个关键方面的基本理解， 生物学了解iNKT细胞发育的关键方面将最终使改变细胞的生长成为可能。 这些细胞的功能使用基因治疗的方法，努力控制癌症和其他疾病。

项目成果

A transgenic TCR directs the development of IL-4+ and PLZF+ innate CD4 T cells.

转基因 TCR 指导 IL-4 和 PLZF 先天 CD4 T 细胞的发育。

• DOI: 10.4049/jimmunol.1300862
• 发表时间: 2013
• 期刊: Journal of immunology (Baltimore, Md. : 1950)
• 作者: Zhu,Lingqiao;Qiao,Yu;Choi,EstherS;Das,Joy;Sant'angelo,DerekB;Chang,Cheong-Hee
• 通讯作者: Chang,Cheong-Hee

Direct identification of rat iNKT cells reveals remarkable similarities to human iNKT cells and a profound deficiency in LEW rats.

对大鼠 iNKT 细胞的直接鉴定揭示了与人类 iNKT 细胞的显着相似性以及 LEW 大鼠中的严重缺陷。

• DOI: 10.1002/eji.201242565
• 发表时间: 2013
• 期刊: European journal of immunology
• 影响因子: 5.4
• 作者: Monzon-Casanova,Elisa;Paletta,Daniel;Starick,Lisa;Müller,Ingrid;Sant'Angelo,DerekB;Pyz,Elwira;Herrmann,Thomas
• 通讯作者: Herrmann,Thomas

The Transcription Factor PLZF Is Necessary for the Development and Function of Mouse Basophils.

• DOI: 10.4049/jimmunol.1900068
• 发表时间: 2019-09-01
• 期刊: Journal of immunology (Baltimore, Md. : 1950)
• 作者: Zhang S;Vieth JA;Krzyzanowska A;Henry EK;Denzin LK;Siracusa MC;Sant'Angelo DB
• 通讯作者: Sant'Angelo DB

The BTB-zinc finger transcriptional regulator PLZF controls the development of invariant natural killer T cell effector functions.

• DOI: 10.1038/ni.1641
• 发表时间: 2008-09
• 期刊: Nature immunology
• 影响因子: 30.5

Altered development of NKT cells, γδ T cells, CD8 T cells and NK cells in a PLZF deficient patient.

• DOI: 10.1371/journal.pone.0024441
• 发表时间: 2011
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Eidson M;Wahlstrom J;Beaulieu AM;Zaidi B;Carsons SE;Crow PK;Yuan J;Wolchok JD;Horsthemke B;Wieczorek D;Sant'Angelo DB
• 通讯作者: Sant'Angelo DB