Immune regulation by thymocyte-selected CD4 T cells

描述(申请人提供)：最近，我们发现了一种新的CD4T细胞发育途径，它是由表达MHC II类胸腺细胞介导的。这一发现为人类CD4T细胞发育的几个无法解释的观察结果提供了答案。人类胸腺细胞表达MHC II类，并能介导CD4T细胞的选择，因此在人类中可能存在两种CD4T细胞群，而在小鼠中则不存在。我们将胸腺细胞选择的CD_4细胞命名为T-CD_4(胸腺细胞选择)，另一种命名为E-CD_4(上皮细胞选择)，以反映它们的选择途径。在建立了CD4T细胞的新的发育途径后，我们开始研究T-CD4T细胞的功能。我们的初步数据表明，CD4T细胞具有不同的细胞因子产生潜力，这取决于它们的选择途径。与E-CD4T细胞不同，T-CD4T细胞可在激活后立即产生辅助性T细胞(Th)1和2细胞因子。对T-CD4T细胞的进一步检查表明，即使在倾斜到Th1细胞后，它们也会产生IL-4和干扰素-3。这种效应表型是在胸腺获得的，值得注意的是，它独立于STAT6。有趣的是，这些特征也在NKT细胞中发现，这些细胞也是胸腺细胞上选择的。然而，T-CD4T细胞不同于NKT细胞，因为T-CD4T细胞需要MHC-II-肽复合体的形成，不表达NK1.1，并且有不同的TCR谱系。我们的新发现增加了人类T细胞介导的免疫反应的另一个复杂程度。因此，了解E-和T-CD4T细胞群之间的异同，研究T-CD4T细胞在免疫应答中的作用是非常重要的。因此，目前应用的目标是深入研究T-CD4T细胞。目标1将通过采用包括DNA微阵列分析在内的几种策略来确定它们与E-CD4T细胞的不同或相似程度。在目标2中，我们将研究T-CD4T细胞是否在体内启动类似于E-CD4T细胞的免疫反应。我们将研究T-CD4T细胞是否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-CD4T细胞的存在调节特应性疾病发展的假设。我们将通过研究T-CD4T细胞在呼吸道炎症中的作用来检验这一假说。本研究的结果将有助于我们对T-CD4T细胞的理解，这将有助于我们研究T-CD4T细胞在人类免疫疾病中的作用。公共卫生相关性：维持功能免疫系统对人类福祉至关重要。这需要几种类型的免疫细胞，其中一种叫做CD4T细胞。目前的研究应用将研究CD4T细胞功能受选择途径的调控，以更好地了解免疫调节。

DESCRIPTION (provided by applicant): 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-3 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. PUBLIC HEALTH RELEVANCE: The maintenance of the functional immune system is critical for the wellbeing of humans. This requires several types of immune cells and one of them is called CD4 T cell. The current research application will investigate the regulation of CD4 T cell function governed by the selection pathway to have a better understanding of immune regulation.