Control of Lineage Commitment in Developing Thymocytes

胸腺细胞发育中谱系定型的控制

• 批准号: 8212191
• 负责人: Dietmar J Kappes
• 金额: $ 44.83万
• 依托单位: RESEARCH INST OF FOX CHASE CAN CTR
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-06-01 至 2015-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8212191
• 关键词: Address; Adoptive Transfer; Adult; Affect; Affinity; Age; Animals; Antibodies; Blood Cells; CD4 Positive T Lymphocytes; CD44 gene; CD8B1 gene; Cell Differentiation process; Cell Lineage; Cell Maturation; Cells; Cessation of life; Characteristics; Childhood Leukemia; Data; Defect; Development; Disease; Employee Strikes; Event; Exhibits; Fetus; Genetic; Genetic Transcription; Growth; Health; Hematopoietic; Human; In Vitro; Incidence; Ligands; Lymphoid; Lymphoma; Lymphomagenesis; Maintenance; Malignant Neoplasms; Mediating; Mediator of activation protein; Modeling; Monoclonal Antibody HuM291; Mus; Mutation; Oncogenes; Phenotype; Physiological; Play; Population; Process; Regulatory Element; Reporter; Role; Series; Signal Transduction; Staging; T-Cell Development; T-Lymphocyte; Testing; Thymic Lymphoma; Thymocyte Development; Thymocyte Selection; Thymus Gland; Transgenes; Transgenic Mice; Transgenic Organisms; True Thymic Hyperplasia; Tumor Suppressor Genes; Ursidae Family; base; cell type; fetal; in utero; in vivo; in vivo Model; monolayer; novel; premature; public health relevance; research study; response; single cell analysis; thymocyte; transcription factor; tumor; tumor initiation

DESCRIPTION (provided by applicant): Hitherto, the expression of ThPOK in T cell development was believed to be restricted to the ab T cell lineage, in particular to transitional CD4+8lo thymocytes and SP CD4 cells in the thymus and periphery. We now show that a subset of gdTCR+ thymocytes also expresses ThPOK, and that ThPOK expression correlates largely with expression of the activation marker CD44. Furthermore, ThPOK is expressed in KN6 gdTCR transgenic mice in the presence of high but not low affinity ligands. These observations suggest that ThPOK is induced in gd thymocytes in response to strong TCR signals. Significantly, HD-/- mice, which lack functional ThPOK, show a severe defect in development of mature gd thymocytes, while mice expressing ThPOK constitutively show a striking increase, establishing an important role for ThPOK in maturation and/or lineage commitment of gd cells. Given that the importance of TCR signaling and selection for gd development remains highly controversial, establishing a critical role for ThPOK in these processes would represent a significant advance. Hence in Aims 1 and 2 of the current proposal, we propose to address whether ThPOK induction in gd thymocytes is directly regulated by TCR signaling, and whether ThPOK controls positive/negative selection of gd thymocytes and/or commitment to the gd lineage. Interestingly, while ThPOK appears to be required for normal gd development, its expression in preTCR-expressing DN thymocytes leads to a high incidence of thymic lymphomas. In Aim 3 we propose to identify the cell type and stage in ontogeny at which lymphomagenesis is initiated, and test whether gdTCR expression or gd commitment are sufficient to protect DN thymocytes against ThPOK-mediated lymphomagenesis. PUBLIC HEALTH RELEVANCE: The current proposal deals with the process by which T cells develop to the distinct gd lineage, which we show is controlled by a key transcription factor called ThPOK. How ThPOK controls this process is unknown and the subject of this proposal. Unregulated expression of ThPOK causes blood cell cancer, so that understanding its function is of direct relevance to health.

描述(由申请人提供)：迄今为止，T细胞发育中ThPOK的表达被认为限于ab T细胞谱系，特别是胸腺和外周中的过渡性CD4+8lo胸腺细胞和SP CD4细胞。我们现在表明 gdTCR+ 胸腺细胞的一个子集也表达 ThPOK，并且 ThPOK 表达在很大程度上与激活标记 CD44 的表达相关。此外，ThPOK 在高亲和力配体存在但不存在低亲和力配体的情况下在 KN6 gdTCR 转基因小鼠中表达。这些观察结果表明，gd 胸腺细胞响应强 TCR 信号而诱导 ThPOK。值得注意的是，缺乏功能性 ThPOK 的 HD-/- 小鼠在成熟 gd 胸腺细胞的发育中表现出严重缺陷，而表达 ThPOK 的小鼠则表现出显着的增加，从而确立了 ThPOK 在 gd 细胞成熟和/或谱系定型中的重要作用。鉴于 TCR 信号传导和选择对 gd 发育的重要性仍然存在很大争议，确定 ThPOK 在这些过程中的关键作用将代表着重大进步。因此，在当前提案的目标1和2中，我们建议解决gd胸腺细胞中的ThPOK诱导是否直接受TCR信号调节，以及ThPOK是否控制gd胸腺细胞的正/负选择和/或对gd谱系的承诺。有趣的是，虽然 ThPOK 似乎是正常 gd 发育所必需的，但其在表达 preTCR 的 DN 胸腺细胞中的表达导致胸腺淋巴瘤的高发病率。在目标 3 中，我们建议鉴定淋巴瘤发生起始的细胞类型和个体发育阶段，并测试 gdTCR 表达或 gd 定型是否足以保护 DN 胸腺细胞免受 ThPOK 介导的淋巴瘤发生。 公共健康相关性：当前提案涉及 T 细胞发育成独特 gd 谱系的过程，我们表明该谱系由称为 ThPOK 的关键转录因子控制。 ThPOK 如何控制此过程尚不清楚，也是本提案的主题。 ThPOK 表达失控会导致血细胞癌，因此了解其功能与健康直接相关。