SOX4 and SOX13 control early steps of invariant NKT cell differentiation

SOX4 和 SOX13 控制恒定 NKT 细胞分化的早期步骤

基本信息

批准号：
8709664
负责人：
Joonsoo Kang
金额：
$ 25.13万
依托单位：
UNIV OF MASSACHUSETTS MED SCH WORCESTER
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-07-01 至 2016-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8709664
关键词：
1-Phosphatidylinositol 3-Kinase AKT Signaling Pathway Accounting Animals Antigen Receptors Antigens Asthma Atherosclerosis Autoimmunity B-Lymphocytes Boxing CD3 Antigens CD44 gene CD8B1 gene Cancer Vaccines Cell Differentiation process Cell Lineage Cell physiology Cells Clinical Research Clinical Trials Commit Development Disease Environment Exhibits Gene Expression Profile Gene Rearrangement Gene Targeting Generations Genes Genetic Recombination Histocompatibility Antigens Class I Hour Immune response Immunity Immunosuppression Immunotherapy Impairment Infection Inflammatory Institutes Interferons Interleukin-10 Interleukin-17 Interleukin-4 Intestines Link Lipids Locales Lymphocyte Lymphocyte Subset Lymphoid Lymphoid Cell Malignant Neoplasms Mediating Metabolic MicroRNAs Molecular Mucous Membrane Mus Myelogenous Myeloid Cells Natural Immunity Natural Killer Cells Organ Phenotype Production Proto-Oncogene Protein c-kit Reaction Recruitment Activity Regulator Genes Reporter Siblings Signal Transduction Specific qualifier value Staging Stress T-Cell Development T-Lymphocyte T-Lymphocyte Subsets Testing Thymocyte Development Tissues Virus Diseases adaptive immunity base cancer therapy catalyst cell type combinatorial cytotoxic design fitness immune function innate immune function intraepithelial mucosa-associated lymphoid tissue novel pathogen progenitor programs promoter public health relevance response theories thymocyte transcription factor tumor vaccine efficacy

项目摘要

DESCRIPTION (provided by applicant): Invariant NKT (iNKT) cells expressing the canonical V?14-J?18 TCR are central to early immune responses to altered environments potentially damaging to the host. This fast response conditions subsequent activities of diverse lymphoid and myeloid cell subsets. Thus, targeted modulations of iNKT cells have emerged as a potential approach to treat inflammatory disorders as well as enhancing immunity to tumors and vaccines. iNKT cells recognize lipid antigens in the context of the non-classical MHC Class I molecule CD1d. The rapid effector capabilities of iNKT cells, often referred to as "innate-like" responses, are programmed intrathymically and are fundamentally different from the adaptive immunity mediated by the conventional ??T cells. The intrathymic programming of iNKT cell function has been shown to dependent on the signaling of the canonical TCR, and by extension, it has been assumed that TCR signals commit a common precursor of ??T cells to become innate like. However, iNKT cells share molecular features with other innate-like lymphocytes such as ??T cells and genes that control iNKT cell development are modulated by signals other than TCR. We observed that mice lacking the High Mobility Group box (HMG) transcription factors (TFs) Sox4 or Sox13 are impaired in the generation of iNKT and innate-like ??T cell subsets, but not conventional adaptive ??T cells. Both TFs are expressed prior to Tcr gene rearrangements, and in other cell types, combinatorial activities of HMG TFs dictate cell lineage identity and function. Sox13 is exclusively expressed in iNKT and ??TCR+ thymocyte subsets during the programming of effector function and prior to thymic egress. Sox13 is also expressed in half of early T cell progenitors, raising the possibility that Sox13+ progenitors may be biased to generate innate-like effectors expressing either ??TCR or ??TCR. To test this alternate mode of iNKT differentiation, we have developed and validated Sox13 reporter mice. This proposal will determine whether Sox13 and Sox4 function in an innate lymphoid lineage committed precursor to program the rapid effector potential of iNKT cells.

描述（由申请人提供）：表达典型 V?14-J?18 TCR 的不变 NKT (iNKT) 细胞对于对可能损害宿主的改变环境的早期免疫反应至关重要。这种快速反应决定了不同淋巴和骨髓细胞亚群的后续活动。因此，iNKT 细胞的靶向调节已成为治疗炎症性疾病以及增强对肿瘤和疫苗的免疫力的潜在方法。 iNKT 细胞在非经典 MHC I 类分子 CD1d 的背景下识别脂质抗原。 iNKT 细胞的快速效应能力，通常被称为“先天样”反应，在胸腺内编程，与传统 NKT 细胞介导的适应性免疫有根本不同。 iNKT 细胞功能的胸腺内编程已被证明依赖于经典 TCR 的信号传导，并且推而广之，人们假设 TCR 信号使 T 细胞的共同前体成为先天性的。然而，iNKT 细胞与其他先天样淋巴细胞（例如 T 细胞）具有相同的分子特征，并且控制 iNKT 细胞发育的基因受 TCR 以外的信号调节。我们观察到，缺乏高迁移率组盒（HMG）转录因子（TF）Sox4 或 Sox13 的小鼠在 iNKT 和先天性 T 细胞亚群的生成方面受到损害，但传统的适应性 T 细胞却没有受到损害。两种 TF 在 Tcr 基因重排之前表达，在其他细胞类型中，HMG TF 的组合活性决定细胞谱系身份和功能。 Sox13 在效应功能编程期间和胸腺排出之前仅在 iNKT 和 TCR+ 胸腺细胞亚群中表达。 Sox13 也在一半的早期 T 细胞祖细胞中表达，这增加了 Sox13+ 祖细胞可能偏向产生表达 αTCR 或 αTCR 的先天样效应子的可能性。为了测试这种 iNKT 分化的替代模式，我们开发并验证了 Sox13 报告小鼠。该提案将确定 Sox13 和 Sox4 是否在先天淋巴谱系定向前体中发挥作用，以编程 iNKT 细胞的快速效应潜力。