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

• 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
• 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

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）：表达经典V？14-J 18 TCR是对可能损害宿主的改变的环境的早期免疫应答的核心。这种快速反应调节了不同淋巴细胞和骨髓细胞亚群的后续活动。因此，iNKT细胞的靶向调节已经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CD 1d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“先天性”反应，是胸腺内编程的，与传统免疫系统介导的适应性免疫有根本不同。T细胞。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，并且通过扩展，已经假设TCR信号承诺共同的？T细胞变成先天性的。然而，iNKT细胞与其他先天性淋巴细胞如？控制iNKT细胞发育的T细胞和基因由TCR以外的信号调节。我们观察到，缺乏高迁移率族盒（HMG）转录因子（TF）Sox 4或Sox 13的小鼠在iNKT和先天样？T细胞亚群，但不是传统的适应性？T细胞。两种TF在Tcr基因重排之前表达，并且在其他细胞类型中，HMG TF的组合活性决定细胞谱系身份和功能。Sox 13只在iNKT和？TCR+胸腺细胞亚群在效应子功能编程期间和胸腺排出之前。Sox 13也在一半的早期T细胞祖细胞中表达，这增加了Sox 13+祖细胞可能偏向于产生先天性样效应子的可能性，这些效应子表达？TCR还是？TCR。为了测试iNKT分化的这种替代模式，我们开发并验证了Sox 13报告小鼠。该提案将确定Sox 13和Sox 4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。