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: 9208107
• 负责人: Hai-Hui Xue
• 金额: $ 38.13万
• 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/9208107
• 关键词: Acute; Acute T Cell Leukemia; Adult; Aging; Animal Model; Antigens; Bacteria; CD4 Positive T Lymphocytes; CD40 Ligand; CD8-Positive T-Lymphocytes; CD8B1 gene; Cell Lineage; Cells; Cellular Immunity; Diagnosis; Ensure; Enterobacteria phage P1 Cre recombinase; Epigenetic Process; Etiology; FOXP3 gene; Gene Targeting; Genes; Hematopoietic stem cells; 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; 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; new therapeutic target; notch protein; novel strategies; pathogen; progenitor; public health relevance; reconstitution; seal; thymocyte; tool; transcription factor; transcriptome; 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(申请人提供)：免疫缺陷(遗传性或获得性)和淋巴细胞恶性是两种严重威胁公共健康的主要免疫疾病。首先，成人T细胞的丧失(例如，由于化疗或衰老)严重损害细胞免疫。如何建立和维持不同的CD4+和CD8+T细胞特性目前仍是一个未解之谜。其次，急性T细胞淋巴母细胞性白血病/淋巴瘤(T-ALL)是由胸腺内发育中的T细胞转化引起的。为了改进诊断和开发新的靶向治疗方法，需要阐明T-ALL启动和传播的因素/途径。Tcf1和Lef1转录因子在T细胞发育中起着重要的作用。我们还表明，Tcf1通过抑制Lef1和Notch在早期胸腺细胞中的表达而发挥肿瘤抑制作用。Tcf1和Lef1与Wnt-？-catenin通路密切相关；然而，关于？？-catenin在T细胞发育和恶性肿瘤中的生理作用的长期争论仍未解决。通过有条件地将Tcf1和Lef1同时靶向CD4+CD8+双阳性(DP)胸腺细胞，我们发现Tcf1/Lef1双缺陷CD8+T细胞在没有预先激活的情况下，表现出包括CD4辅受体本身、CD40配体、Rorgt和Foxp3在内的CD4+谱系基因的异常表达。我们假设Tcf1和Lef1通过表观遗传沉默CD4+相关基因来封闭CD8+T细胞的特性。我们已经产生了一个真正的ç-catenin缺失突变体和另一个小鼠品系，其中Tcf1长亚型被消融，因此Tcf1-ç-catenin相互作用被取消。通过这些新的工具，我们将检验Tcf1和Lef1使用？连环蛋白依赖和独立的机制来调节胸腺细胞成熟和转化的假设。我们的具体目的是：1.研究Tcf1和Lef1调节CD8+T细胞表型的机制。具体目的2.阐明B-连环蛋白及其与Tcf1/Lef1的相互作用在T细胞发育和恶性转化中的作用。这些研究将确定第一批转录因子及其与负责调节CD8+T细胞特性的表观遗传机制的相互作用。新的动物模型将确保前所未有的清晰度，以解决围绕ç-catenin的长期争议。这一结果将建立免疫细胞识别和参与Wnt-ü-catenin途径的新范式。这些信息将确定引导造血祖细胞或iPS细胞向具有所需抗原特异性的成熟T细胞转化的关键调节点，从而有助于改善免疫重建和靶向、基于细胞的癌症治疗。