Tcf/Lef-b-catenin in T cell identity and cancer

Tcf/Lef-b-连环蛋白在 T 细胞身份和癌症中的作用

• 批准号: 8883981
• 负责人: Hai-Hui Xue
• 金额: $ 37.75万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-03-15 至 2019-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8883981
• 关键词: Acute; Adult; Age; Animal Model; Antigens; Bacteria; CD4 Positive T Lymphocytes; CD40 Ligand; CD8B1 gene; Cell Lineage; Cells; Cellular Immunity; Diagnosis; Ensure; Epigenetic Process; Etiology; Gene Expression Profile; Gene Targeting; Genes; Hematopoietic; Immune; Immune System Diseases; Immune response; Immunologic Deficiency Syndromes; Infection Control; Inherited; Knowledge; Lymphoblastic Leukemia; Lymphocyte; Malignant - descriptor; Malignant Neoplasms; Mature T-Lymphocyte; Methyltransferase; Modeling; Mouse Strains; Outcome; Pathway interactions; Physiological; Process; Production; Protein Isoforms; Public Health; Published Comment; Recruitment Activity; Regulation; Role; Specific qualifier value; Specificity; Staging; T-Cell Development; T-Lymphocyte; Testing; Thymus Gland; Tumor Suppression; Tumor Suppressor Proteins; Virus; base; beta catenin; cancer therapy; chemotherapy; cytotoxic; genetic analysis; histone modification; improved; induced pluripotent stem cell; leukemia/lymphoma; mutant; notch protein; novel; novel strategies; pathogen; progenitor; public health relevance; recombinase; reconstitution; seal; targeted treatment; thymocyte; tool; transcription factor; translational medicine

 DESCRIPTION (provided by applicant): Immunodeficiencies (inherited or acquired) and lymphocyte malignancy are two major immune disorders that pose grave threats to public health. Firstly, loss of T cells in adults (e.g. due to chemotherapy or ageing) severely compromises cellular immunity. How the distinct CD4+ and CD8+ T cell identities are established and maintained remains an unanswered puzzling question at present. Secondly, acute T cell lymphoblastic leukemia/lymphomas (T-ALLs) is induced by the transformation of developing T cells in the thymus. Elucidation of factors/pathways contributing to initiation and propagation of T-ALLs is required to improve diagnosis and develop novel targeted therapies. Tcf1 and Lef1 transcription factors are well documented to have essential roles in T cell development. We also showed that Tcf1 functions as a tumor suppressor by restraining Lef1 and Notch expression in early thymocytes. Tcf1 and Lef1 are most notably associated with the Wnt-ß-catenin pathway; however, the long- standing controversies regarding the physiological roles of ß-catenin in T cell development and malignancy remain unresolved. By conditionally targeting both Tcf1 and Lef1 at CD4+CD8+ double positive (DP) thymocytes, we found that Tcf1/Lef1 double deficient CD8+ T cells showed inappropriate expression of CD4+ lineage genes including the CD4 coreceptor itself, CD40 ligand, Rorgt and Foxp3 without prior activation. We hypothesize that Tcf1 and Lef1 seal off CD8+ T cell identity by epigenetically silencing CD4+-associated genes. We have generated a true ß-catenin null mutant and another mouse strain where Tcf1 long isoforms are ablated and hence Tcf1-ß- catenin interaction is abrogated. With these new tools, we will test the hypothesis that Tcf1 and Lef1 use both ß-catenin-dependent and -independent mechanisms to regulate thymocyte maturation and transformation. Our specific aims are: Specific Aim 1. To investigate the mechanisms by which Tcf1 and Lef1 regulate CD8+ T cell identity. Specific Aim 2. To elucidate the requirements of ß-catenin and its interaction with Tcf1/Lef1 in T cell development and malignancy. These studies will identify the first transcription factors and their interaction with epigenetic machinery that re responsible for regulation of CD8+ T cell identity. The new animal models will ensure unprecedented clarity to resolve the long-standing controversies over ß-catenin. The outcomes will establish new paradigms in immune cell identity and the involvement of Wnt-ß-catenin pathway. The information will identify critical regulatory points in directing hematopoietic progenitors or iPS cells to mature T cells with desired antigen specificity and thus help improve immune reconstitution and targeted, cell-based cancer therapy.

 描述（由适用提供）：免疫缺陷（继承或获得）和淋巴细胞恶性肿瘤是对公共卫生构成严重威胁的两个主要免疫疾病。首先，成年人中T细胞的丧失（例如，由于化学疗法或衰老引起的）严重损害了细胞免疫学。目前，如何建立和维持一个未解决的拼图问题，如何建立和维持不同的CD4+和CD8+ T细胞身份。其次，急性T细胞淋巴细胞白血病/淋巴瘤（T-Alls）是由胸腺中发育细胞的转化引起的。需要阐明有助于促进和传播的因素/途径，以改善诊断和发展新颖的靶向疗法。 TCF1和LEF1转录因子已充分记录在T细胞发育中具有重要作用。我们还表明，TCF1通过限制早期胸腺细胞的LEF1和Notch表达来充当肿瘤抑制器。 TCF1和LEF1与Wnt-ß-catenin途径相关。然而，关于ß-catenin在T细胞发育和恶性肿瘤中的身体作用的长期争议仍未解决。通过有条件地靶向CD4+ CD8+双阳性（DP）胸腺细胞的TCF1和LEF1，我们发现TCF1/LEF1双缺陷CD8+ T细胞表现出不适当的CD4+谱系基因表达，包括CD4 colector本身，CD40 Ligand，Rorgt，Rorgt和Fox没有先验的激活激活。我们假设TCF1和LEF1通过表观遗传沉默的CD4+相关基因密封CD8+ T细胞身份。我们已经产生了一个真实的ß-catenin null突变体和另一种小鼠菌株，其中TCF1长同工型被消融，因此TCF1-ß-catenin相互作用被废除。借助这些新工具，我们将检验以下假设：TCF1和LEF1同时使用β-catenin依赖性和非依赖性机制来调节胸腺细胞的成熟和转化。我们的具体目的是：特定目的1。研究TCF1和LEF1调节CD8+ T细胞身份的机制。具体目的2。阐明β-catenin的要求及其与TCF1/LEF1在T细胞发育和恶性肿瘤中的相互作用。这些研究将确定第一个转录因子及其与表观遗传机制的相互作用，以调节CD8+ T细胞身份。新的动物模型将确保前所未有的清晰度，以解决有关β-catenin的长期争议。结果将在免疫细胞同一性和WNT-ß-catenin途径的参与方面建立新的范式。该信息将在指导造血祖细胞或IPS细胞的关键调节点以具有所需的抗原特异性为成熟的T细胞，从而有助于改善免疫结构并靶向基于细胞的癌症治疗。