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）：表达规范V？14-J？？18 TCR的不变性NKT（inkt）细胞是对改变宿主可能损害的改变环境的早期免疫反应的中心。这种快速响应的条件随后的不同淋巴样和髓样细胞亚群的活性。因此，靶向的INKT细胞的靶向调节已成为治疗炎症性疾病的潜在方法，并增强了对肿瘤和疫苗的免疫力。 Inkt细胞在非经典MHC I类CD1D的背景下识别脂质抗原。 Inkt细胞的快速效应能力（通常称为“先天性”反应）在胸前进行了编程，并且与常规?? T细胞介导的适应性免疫有根本不同。 Inkt细胞功能的胸膜弹性编程已被证明取决于规范TCR的信号传导，并且逐渐假定TCR信号会构成一个tcr的共同前体。但是，Inkt细胞与其他先天样淋巴细胞（例如？T细胞和控制Inkt细胞发育的基因）共享分子特征，该基因受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（TFS）SOX4或SOX13的小鼠在inkt和先天性的？两个TF在TCR基因重排之前表达，在其他细胞类型中，HMG TF的组合活性决定了细胞谱系的身份和功能。 Sox13在效应子函数编程过程中和胸腺出口之前专门在inkt和ktcr+胸腺集中表达。 Sox13也以早期T细胞祖细胞的一半表达，从而提高了Sox13+祖细胞可能会偏向于产生表达?? TCR或?? TCR的先天效应器的可能性。为了测试这种互动分化的替代模式，我们已经开发并验证了Sox13报告基因小鼠。该建议将确定Sox13和Sox4是否在先天淋巴谱系中功能是否功能，以编程Inkt细胞的快速效应潜力。