Immune regulation by thymocyte-selected CD4 T cells

摘要 最近，我们揭示了一种新的CD4T细胞发育途径，即 由表达MHC-II类的胸腺细胞介导。这一发现提供了一个答案 对人类CD4T细胞发育的几个无法解释的观察。人类 胸腺细胞表达MHC-II类，并能介导CD4T细胞选择，因此 人类可能存在两个CD4T细胞群，但小鼠中没有。我们命名为 胸腺细胞选择的CD_4细胞T-CD_4(胸腺细胞选择的)和其他E-CD_4 (上皮细胞选择)以反映它们的选择途径。建立了新的 对于CD4T细胞的发育途径，我们已经开始研究T细胞的功能。 CD4T细胞。我们的初步数据显示，CD4T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。不同于E-CD4T 细胞，T-CD4T细胞可立即产生辅助性T细胞(Th)1和2细胞因子 激活。进一步检查T-CD4T细胞发现，它们在体内产生IL-4 即使在偏向Th1细胞后，也会添加干扰素。此效应器表型为 在胸腺中获得，值得注意的是，它独立于STAT6。有趣的是，这些 在NKT细胞中也发现了特征，这些细胞也是胸腺细胞上选择的。 然而，T-CD4T细胞与NKT细胞不同，因为T-CD4T细胞需要MHC II类-多肽复合体发育，不表达NK1.1，并具有多样性的TCR 曲目。我们的新发现增加了T细胞介导的免疫的另一个复杂程度 人类的反应。正因为如此，了解它们之间的相似性和 E-和T-CD4T细胞亚群的差异及T-CD4T细胞功能的研究 免疫应答期间的CD4T细胞。因此，当前的目标是 应用是对T-CD4T细胞进行深入研究。目标1将确定他们在多大程度上 通过采用几种策略与E-CD4T细胞不同或相似，包括 DNA微阵列检测。在目标2中，我们将研究T-CD4T细胞是否安装在 体内免疫反应类似于E-CD4T细胞。我们将调查T-CD4T 细胞调节其他免疫细胞的功能以及T-CD4T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验证这一假设 研究T-CD4T细胞在呼吸道炎症中的作用。结果是 这项拟议的研究将为我们理解T-CD4T细胞提供见解， 这将有助于我们研究T-CD4T细胞在人类免疫疾病中的作用。

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 T- CD4 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 T- CD4 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 inflammation. 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.