Immune regulation by thymocyte-selected CD4 T cells

胸腺细胞选择的 CD4 T 细胞的免疫调节

• 批准号: 7614833
• 负责人: Cheong-Hee Chang
• 金额: $ 35.7万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-04-01 至 2008-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7614833
• 关键词: Allogenic; Bare Lymphocyte Syndromes; Biological Assay; CD4 Positive T Lymphocytes; Cell Differentiation process; Cells; Characteristics; Class; Complex; DNA Microarray Chip; DNA Microarray format; Data; Defect; Dendritic Cells; Depth; Development; DiGeorge Syndrome; Disease; Disease model; Epithelial Cells; Gene Expression; Generations; Goals; Hematopoietic; Human; Immune; Immune System Diseases; Immune response; Immunodeficient Mouse; Immunologic Deficiency Syndromes; Interferons; Interleukin-4; MHC Class II Genes; Mediating; Memory; Mus; Names; Numbers; Outcome; Pathway interactions; Patients; Peptides; Phenotype; Population; Production; Property; Regulation; Role; T-Cell Development; T-Lymphocyte; Testing; Th1 Cells; Th2 Cells; Thymic Tissue; Thymic epithelial cell; Thymus Gland; Transplantation; abstracting; airway hyperresponsiveness; airway inflammation; base; cell mediated immune response; cytokine; immune function; in vitro Assay; in vivo; insight; mouse model; protective effect; response; thymocyte; transcription factor

Abstract Recently, we have revealed a new developmental pathway for CD4 T cells that is mediated by MHC class II expressing thymocytes. This finding provided an answer for several unexplainable observations of CD4 T cell development in humans. Human thymocytes express MHC class II and can mediate CD4 T cell selection and therefore two CD4 T cell populations are likely present in humans but not in mice. We named thymocyte-selected CD4 cells T-CD4 (Thymocyte-selected) and the other E-CD4 (Epithelial cell-selected) to reflect their selection pathway. Having established the new developmental pathway for CD4 T cells, we have begun investigating the function of TCD4 T cells. Our preliminary data demonstrate that CD4 T cells possess a different cytokine production potential depending on their selection pathway. Unlike E-CD4 T cells, T-CD4 T cells can produce T helper (Th) 1 and 2 cytokines immediately after activation. Further examinations of T-CD4 T cells revealed that they make IL-4 in addition to IFN-? even after being skewed to Th1 cells. This effector phenotype is acquired in the thymus and, remarkably, independent of Stat6. Interestingly, these characteristics are also found in NKT cells that are also selected on thymocytes. However, T-CD4 T cells are distinct from NKT cells since T-CD4 T cells require MHC class II-peptide complexes to develop, do not express NK1.1, and have a diverse TCR repertoire. Our new findings add another level of complexity in T cell mediated immune responses in humans. Because of this, it is important to know the similarities and the differences between E- and T-CD4 T cell population and to investigate the function of TCD4 T cells during an immune response. Accordingly, the goal of the current application is to study T-CD4 T cells in depth. Aim 1 will determine to what extent they are different from or similar to E-CD4 T cells by employing several strategies including the DNA microarray assay. In Aim 2, we will study whether T-CD4 T cells mount an immune response in vivo similar to E-CD4 T cells. We will investigate whether T-CD4 T cells regulate the function of other immune cells and whether T-CD4 T cells can become memory cells. The last Aim will test the hypothesis that the presence of T-CD4 T cells regulates the development of atopic diseases. We will test this hypothesis by examining the role of T-CD4 T cells in the context of airway hyperreactivity. The outcome of the proposed study will provide insights toward our understanding of T-CD4 T cells, which will help us to investigate T-CD4 T cells in immune diseases in human.

抽象的 最近，我们揭示了 CD4 T 细胞的新发育途径，即 由表达 MHC II 类胸腺细胞介导。这一发现为以下问题提供了答案 人类 CD4 T 细胞发育的一些无法解释的观察结果。人类 胸腺细胞表达 MHC II 类，可以介导 CD4 T 细胞选择，因此 两种 CD4 T 细胞群可能存在于人类体内，但不存在于小鼠体内。我们命名为 胸腺细胞选择的 CD4 细胞 T-CD4（胸腺细胞选择）和其他 E-CD4 （上皮细胞选择）反映其选择途径。建立新的 CD4 T细胞的发育途径，我们已经开始研究TCD4的功能 T细胞。我们的初步数据表明 CD4 T 细胞具有不同的 细胞因子的产生潜力取决于它们的选择途径。与 E-CD4 T 不同 细胞，T-CD4 T 细胞可以立即产生 T 辅助细胞 (Th) 1 和 2 细胞因子 激活。对 T-CD4 T 细胞的进一步检查表明，它们在以下细胞中产生 IL-4： 除了干扰素-?即使在偏向 Th1 细胞之后。该效应子表型是 在胸腺中获得，并且值得注意的是，独立于 Stat6。有趣的是，这些 NKT 细胞中也发现了这些特征，这些细胞也在胸腺细胞上进行选择。 然而，T-CD4 T 细胞与 NKT 细胞不同，因为 T-CD4 T 细胞需要 MHC II 类肽复合物待开发，不表达 NK1.1，并具有多样化的 TCR 剧目。我们的新发现使 T 细胞介导的免疫变得更加复杂 人类的反应。因此，了解相似之处和不同之处非常重要 E- 和 T-CD4 T 细胞群之间的差异并研究 TCD4 的功能 免疫反应期间的 T 细胞。据此，当前的目标 应用是深入研究T-CD4 T细胞。目标 1 将决定他们在多大程度上 通过采用多种策略，与 E-CD4 T 细胞不同或相似，包括 DNA 微阵列分析。在目标 2 中，我们将研究 T-CD4 T 细胞是否安装 体内免疫反应类似于E-CD4 T细胞。我们将调查T-CD4 T是否 细胞调节其他免疫细胞的功能以及 T-CD4 T 细胞是否可以 成为记忆细胞。最后一个目标将检验 T-CD4 存在的假设 T 细胞调节特应性疾病的发展。我们将通过以下方式检验这个假设 检查 T-CD4 T 细胞在气道高反应性中的作用。这 拟议研究的结果将为我们理解 T-CD4 提供见解 T细胞，这将有助于我们研究T-CD4 T细胞在人类免疫疾病中的作用。