Immune regulation by thymocyte-selected CD4 T cells

描述（由申请人提供）：最近，我们揭示了一种由表达MHC II类的胸腺细胞介导的CD 4 T细胞的新发育途径。这一发现为人类CD 4 T细胞发育的几个无法解释的观察结果提供了答案。人胸腺细胞表达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。我们将胸腺细胞选择的CD 4细胞命名为T-CD 4（Thymocyte-selected）和E-CD 4（Epithelial cell-selected），以反映它们的选择途径。在建立了CD 4 T细胞新的发育途径后，我们开始研究T-CD 4 T细胞的功能。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，这取决于它们的选择途径。与E-CD 4 T细胞不同，T-CD 4 T细胞在活化后可立即产生T辅助细胞（Th）1和2细胞因子。对T-CD 4 T细胞的进一步检查显示，即使在偏向于Th 1细胞后，它们也能产生IL-4和IFN-3。这种效应表型是在胸腺中获得的，并且显著地独立于Stat 6。有趣的是，这些特征也发现在NKT细胞，也选择在胸腺细胞。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-肽复合物来发育，不表达NK1.1，并且具有多样化的TCR库。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性水平。因此，了解E-和T-CD 4 T细胞群之间的相似性和差异并研究T-CD 4 T细胞在免疫应答期间的功能是重要的。因此，本申请的目标是深入研究T-CD 4 T细胞。目的1将通过采用包括DNA微阵列分析在内的多种策略来确定它们与E-CD 4 T细胞的不同或相似程度。在目标2中，我们将研究T-CD 4 T细胞是否在体内产生类似于E-CD 4 T细胞的免疫应答。我们将研究T-CD 4 T细胞是否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 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-CD 4 T细胞在气道炎症中的作用来检验这一假设。该研究结果将有助于我们对T-CD 4 T细胞的理解，这将有助于我们研究T-CD 4 T细胞在人类免疫疾病中的作用。公共卫生相关性：维持功能性免疫系统对人类的健康至关重要。这需要几种类型的免疫细胞，其中一种称为CD 4 T细胞。目前的研究应用将研究由选择途径控制的CD 4 T细胞功能的调节，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.