Cellular and molecular mechanisms of inflammatory T cell regulation.

免疫系统的T细胞在细菌、病毒和肿瘤的作用下迅速增殖。它们通过直接杀死受感染的细胞或吸引其他辅助免疫细胞促进炎症来协调身体对病原体和癌症的反应。由于T细胞可以在感染时以惊人的速度繁殖，并且由于它们产生许多抗菌和抗病毒分子，这些分子可能对身体产生大量毒性，因此严格控制T细胞反应至关重要。因此，T细胞在其表面上表达负信号受体。负表面受体的触发导致T细胞内蛋白质信号传导途径的激活，导致它们死亡或降低其促炎功能。通过这种方式，一旦感染被清除，免疫系统就会避免过度的，不适当的炎症。 这项研究计划的主要目标是确定负信号受体下游的分子通路。我们之前已经确定了一种分子Bat 3，它通过负受体Tim-3停止信号传导。因此，Bat 3促进T细胞驱动的炎症。然而，我们仍然需要了解Bat 3在T细胞中的功能。使用分子和细胞生物学方法的组合，我和我的团队将定义Bat 3运作的分子途径。然后，我们将确定其他与Bat 3结合并影响这些通路的T细胞蛋白。然后，我们将使用尖端技术来确定特定的T细胞生长因子如何影响Bat 3与活细胞中其他分子的结合强度。总的来说，NSERC计划将使我们能够更好地了解介导T细胞反应负调控的分子信号。这些发现将对未来的研究产生直接影响，这些研究旨在创建与维持免疫系统正常功能相关的蛋白质相互作用的分子图谱。该NSERC计划还将确保未来高素质的学生，博士后研究员和研究助理在相关技术的基础研究的培训。

T cells of the immune system proliferate rapidly in response to bacteria, viruses and tumors. They co-ordinate the body's response to pathogens and cancer by either killing infected cells directly, or by attracting other accessory immune cells to promote inflammation. As T cells can multiply at a dramatic rate in response to infection, and as they produce many antimicrobial and antiviral molecules that can be toxic to the body in large amounts, it is crucial that T cell responses be tightly controlled. T cells thus express negative signaling receptors on their surface. Triggering of negative surface receptors leads to the activation of protein signaling pathways within the T cell, causing them to either die or to reduce their pro-inflammatory functions. In this way, the immune system avoids excessive, inappropriate inflammation once an infection has been cleared.  The main goal of this research program is to identify molecular pathways downstream of negative signaling receptors. We have previously identified a molecule, Bat3, that stops signaling via the negative receptor Tim-3. Bat3 thus promotes T cell-driven inflammation. However, there is much that we still need to learn about the function of Bat3 in T cells. Using a combination of molecular and cell biological approaches, my team and I will define the molecular pathways by which Bat3 operates. We will then identify other T cell proteins that bind to Bat3 and that affect these pathways. We will then use cutting edge technology to determine how specific T cell growth factors can influence the strength of binding of Bat3 to other molecules in living cells. Taken together, this NSERC program will allow us to better understand the molecular signals that mediate negative regulation of T cell responses. The findings will have direct implications for future studies aimed at creating a molecular map of protein interactions that are relevant to maintaining proper function of the immune system. This NSERC program will also ensure the training of future highly qualified students, postdoctoral fellows and research assistants in techniques relevant to fundamental research.