Mechanisms generating suppressor CD4 T cells by thymocyte-mediated development

描述（由申请人提供）：对CD 4 T细胞发育的传统理解是，皮质胸腺上皮细胞上的MHC II类分子对于选择是必需的，如小鼠模型所示。然而，临床数据表明，造血干细胞在缺乏MHC II类的患者中重建CD 4 T细胞。在人类中观察到的差异可以通过我们的发现来解释，即CD 4区室被表达MHC II类的胸腺细胞有效地重建，证明了一种新的胸腺细胞驱动的CD 4 T细胞选择途径。我们随后发现，在小鼠中，胸腺细胞选择的CD 4（T-CD 4）T细胞可以在刺激后立即产生Th 1和Th 2细胞因子，这表明它们可能是有效的辅助T细胞。出乎意料的是，具有T-CD 4 T细胞的小鼠免受气道炎症以及实验性过敏性脑脊髓炎的影响。此外，我们的初步数据表明，T-CD 4 T细胞抑制细菌感染后效应CD 4和记忆CD 8 T细胞的产生。总之，T-CD 4 T细胞似乎作为抑制剂参与各种免疫应答。我们的长期目标是了解由T-CD 4 T细胞介导的适应性免疫反应。本申请的目的是研究T-CD 4 T细胞如何抑制其他靶细胞，以及通过胸腺细胞-胸腺细胞（T-T）相互作用的信号传导如何调节T-CD 4 T细胞作为抑制剂的内在功能。中心假设是经由TCR-MHC II类和SLAM-SLAM的T-T相互作用递送独特的信号传导，其改变细胞内环境，导致负责抑制功能的一组基因的激活。基于我们以前的研究和初步数据制定的假设将通过追求两个特定目标进行测试：（1）研究T-CD 4 T细胞作为抑制因子发挥作用的分子机制;（2）确定TCR，SLAM/SAP，IL- 4和MHC II类在产生具有抑制因子功能的CD 4 T细胞中的作用。在目的1中，将对T-CD 4 T细胞介导的抑制功能进行深入分析，以表征T-CD 4 T细胞群并将其与Treg的T细胞群进行比较。在目的2中，将使用BM移植随后进行功能测定来确定T-T相互作用期间信号传导对抑制功能的影响。这项研究具有创新性，因为它研究了一个未被探索的CD 4 T细胞群，该细胞群具有独特而重要的功能。毫无疑问，这项研究具有重要意义，因为它有望揭示T-CD 4 T细胞抑制功能的分子机制。还期望更好地理解T-T相互作用对形成T-CD 4 T细胞库的贡献以及T-CD 4 T细胞的效应器功能。这项研究的结果将为T-CD 4 T细胞如何调节免疫力提供新的见解，并将促进未来T-CD 4 T细胞介导的免疫疗法的临床转化。

DESCRIPTION (provided by applicant): Conventional understanding of CD4 T cell development is that the MHC class II molecules on cortical thymic epithelial cells are necessary for selection, as shown in mouse models. Clinical data, however, demonstrate that hematopoietic stem cells reconstitute CD4 T cells in patients devoid of MHC class II. The difference ob-served in humans can be explained by our discovery that the CD4 compartment is efficiently reconstituted by MHC class II expressing thymocytes, demonstrating a novel thymocyte-driven pathway of CD4 T cell selection. We subsequently showed that, in mice, thymocyte-selected CD4 (T-CD4) T cells can produce both Th1 and Th2 cytokines immediately after stimulation, suggesting that they could be potent helper T cells. Unexpectedly, mice that have T-CD4 T cells are protected from airway inflammation as well as experimental allergic encephalomyelitis. In addition, our preliminary data showed that T-CD4 T cells suppress the generation of effector CD4 and memory CD8 T cells upon bacterial infections. Together, T-CD4 T cells seem to participate in various immune responses as a suppressor. Our long-term goal is to understand adaptive immune responses mediated by T-CD4 T cells. The objective in this application is to investigate how T-CD4 T cells suppress other target cells and how signaling through the thymocyte-thymocyte (T-T) interaction regulates the intrinsic function of T- CD4 T cells as a suppressor. The central hypothesis is that the T-T interaction via TCR-MHC class II and SLAM-SLAM delivers unique signaling, which changes the intracellular environments leading to the activation of a set of genes responsible for the suppressive function. The hypothesis, formulated based on our previous studies and preliminary data, will be tested by pursuing two specific aims: (1) Investigate the molecular mechanisms by which T-CD4 T cells function as a suppressor; and (2) Determine the role of TCR, SLAM/SAP, IL- 4, and MHC class II for the generation of CD4 T cells with the suppressor function. In Aim 1, in depth analyses of the T-CD4 T cell-mediated suppression function will be performed to characterize the T-CD4 T cell population and to compare it with that of Treg. In Aim 2, effects of signaling during the T-T interaction on the suppression function will be ascertained using BM transplantations followed by functional assays. The proposed research is innovative because it investigates an unexplored CD4 T cell population that bears a distinct and significant function. Undoubtedly, the proposed study is significant because it is expected to show the molecular mechanisms for the suppressor function of T-CD4 T cells. It is also expected to obtain a better understanding of the contribution of the T-T interaction to shaping the repertoire of T-CD4 T cells and the effector function of T-CD4 T cells. The outcome of the proposed research will provide new insights into how T-CD4 T cells modulate immunity and will facilitate the clinical translation of T-CD4 T cell mediated immunotherapy in the future.