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CD4 T细胞发育途径，该途径是由表达MHC类胸腺细胞介导的。这一发现为人类CD4 T细胞发育的一些无法解释的观察提供了答案。人胸腺细胞表达MHC II类，并能介导CD4 T细胞的选择，因此在人类中可能存在两种CD4 T细胞群，而在小鼠中不存在。我们将胸腺细胞选择的CD4细胞命名为T-CD4（胸腺细胞选择）和其他E-CD4（上皮细胞选择），以反映它们的选择途径。在建立了CD4 T细胞的新发育途径后，我们开始研究T- CD4 T细胞的功能。我们的初步数据表明，CD4 T细胞具有不同的细胞因子生产潜力，这取决于它们的选择途径。与E-CD4 T细胞不同，T- cd4 T细胞在激活后可以立即产生辅助性T细胞（Th） 1和2细胞因子。对T- cd4 T细胞的进一步检查显示，即使在向Th1细胞倾斜后，它们除了产生IFN-3外，还产生IL-4。这种效应表型是在胸腺中获得的，值得注意的是，它独立于Stat6。有趣的是，这些特征也在胸腺细胞上选择的NKT细胞中发现。然而，T- cd4 T细胞不同于NKT细胞，因为T- cd4 T细胞需要MHC ii类肽复合物才能发育，不表达NK1.1，并且具有多种TCR库。我们的新发现增加了人类T细胞介导的免疫反应的复杂性。因此，了解E- CD4 T细胞群和T-CD4 T细胞群之间的异同以及研究T-CD4 T细胞在免疫应答中的功能是很重要的。因此，当前应用的目标是深入研究T- cd4 T细胞。目的1将通过采用包括DNA微阵列测定在内的几种策略来确定它们与E-CD4 T细胞不同或相似的程度。在Aim 2中，我们将研究T- cd4 T细胞是否在体内产生类似于E-CD4 T细胞的免疫反应。我们将研究T- cd4 T细胞是否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。最后一个目标将测试T- cd4 T细胞的存在调节特应性疾病的发展的假设。我们将通过检查T- cd4 T细胞在气道炎症中的作用来验证这一假设。本研究的结果将为我们对T- cd4 T细胞的认识提供新的见解，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。公共卫生相关性：维持免疫系统的功能对人类的健康至关重要。这需要几种类型的免疫细胞，其中一种叫做CD4 T细胞。目前的研究申请将研究选择途径对CD4 T细胞功能的调控，从而更好地理解免疫调控。

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.