Immune regulation by thymocyte-selected CD4 T cells

摘要 最近，我们发现了一种新的CD 4 T细胞发育途径， 由表达MHC II类的胸腺细胞介导。这一发现为以下问题提供了答案： 人类CD 4 T细胞发育的几个无法解释的观察结果。人类 胸腺细胞表达MHC II类，并可介导CD 4 T细胞选择，因此 两种CD 4 T细胞群可能存在于人类中，但不存在于小鼠中。我们命名 胸腺细胞选择性CD 4细胞T-CD 4（胸腺细胞选择性）和其他E-CD 4 （上皮细胞选择），以反映其选择途径。在建立了新的 CD 4 T细胞的发育途径，我们已经开始研究T细胞的功能， CD 4 T细胞。我们的初步数据表明，CD 4 T细胞具有不同的 细胞因子产生潜力取决于它们的选择途径。与E-CD 4 T不同 细胞，T-CD 4 T细胞可以产生T辅助细胞（Th）1和2细胞因子后立即 activation.对T-CD 4 T细胞的进一步检查显示，它们在体内产生IL-4。 即使在偏向Th 1细胞后，也能增加IFN-γ。这种效应表型是 在胸腺中获得，并且显著地独立于Stat 6。有趣的是，这些 在也在胸腺细胞上选择的NKT细胞中也发现了这些特征。 然而，T-CD 4 T细胞不同于NKT细胞，因为T-CD 4 T细胞需要MHC II类-肽复合物，不表达NK1.1，并具有不同的TCR 保留曲目。我们的新发现增加了T细胞介导的免疫系统的复杂性 人类的反应。正因为如此，重要的是要知道的相似之处和 E-和T-CD 4 T细胞群之间的差异，并研究T- CD 4 T细胞在免疫反应中的作用因此，当前的目标 应用是深入研究T-CD 4 T细胞。目标1将决定他们在多大程度上 与E-CD 4 T细胞不同或相似，采用了几种策略， DNA微阵列分析。在目标2中，我们将研究T-CD 4 T细胞是否能在细胞内表达。 体内免疫应答类似于E-CD 4 T细胞。我们将研究T-CD 4 T 细胞调节其他免疫细胞的功能，以及T-CD 4 T细胞是否可以 成为记忆细胞。最后一个目的是检验T-CD 4的存在是否会导致T-CD 4的表达。 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一假设： 研究T-CD 4 T细胞在气道炎症中的作用。成果 这项研究将为我们理解T-CD 4 T细胞提供见解， 这将有助于我们研究T-CD 4 T细胞在人类免疫性疾病中的作用。

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.