Determining a novel pathway that controls TGF-beta activation in the immune system.

必须迅速动员免疫系统以消除感染，但要严格监管以防止自我有害的免疫反应。当这一规定失效时，动物和人类可能会出现严重的健康问题，如不受控制的感染或自身免疫紊乱(免疫系统攻击人体自身的组织和器官)。由于免疫系统的调节涉及到许多不同的细胞之间的相互通信，所以我们必须了解这种通信所涉及的信号和机制，以了解免疫系统如何维持健康。免疫系统中的一个重要信号由一种名为转化生长因子-β(TGF-β)的蛋白质提供。转化生长因子-β是一种抗炎分子，在调节潜在的有害免疫反应方面很重要。然而，在某些情况下，转化生长因子-β能够促进有害的免疫反应。因此，了解这一关键分子是如何被控制的，对于了解免疫系统是如何被适当调节的至关重要。我们最近的工作强调了一条重要的途径，该途径在控制免疫系统中转化生长因子-β的作用方面至关重要。因此，我们已经证明，当整合素αvβ8受体存在于免疫系统的树突状细胞上时，它会激活转化生长因子-β，从而抑制肠道中的有害免疫反应。此外，在自身免疫和感染模型中，这一途径在促进有害免疫反应方面也很重要。因此，整合素αvβ8在控制多种免疫反应中起着至关重要的作用。然而，目前我们对整合素α-β8-转化生长因子-β途径如何调控不同类型的免疫应答知之甚少，本研究的目的是寻找一种全新的途径来调控免疫应答。此前人们认为这种分子存在于细胞表面。然而，我们现在发现，整合素是由免疫细胞分泌的，这些细胞外小泡能够促进与免疫系统其他细胞的沟通。我们的提案将定义这条途径的重要性，以及如何控制它。这些工作将使我们能够更好地了解调节免疫系统以维持健康的生物机制。

The immune system must be rapidly mobilised to eliminate infection, but be tightly regulated to prevent self-harmful immune responses. When this regulation breaks down, severe health problems can occur in animals and humans such as uncontrolled infection or autoimmune disorders (where the immune system attacks the body's own tissues and organs). As regulation of the immune system involves many different cells communicating with each other, it is essential that we understand the signals and mechanisms involved in this communication to understand how the immune system maintains health.An important signal in the immune system is provided by a protein called transforming growth factor-beta (TGF-beta). TGF-beta acts as an anti-inflammatory molecule, important in regulating potentially harmful immune responses. However, in some scenarios TGF-beta is capable of promoting harmful immune responses. Hence, understanding how this key molecule is controlled is essential in understanding how the immune system is properly regulated. Our recent work has highlighted an important pathway that is crucial in controlling the actions of TGF-beta in the immune system. Thus, we have shown that a receptor called integrin alphav beta8, when present on cells of the immune system called dendritic cells, activates TGF-beta to suppress harmful immune responses in the intestine. Additionally, this pathway is important in promoting harmful immune responses during models of autoimmunity and infection. Hence, integrin alphav beta8 is vital in controlling diverse immune responses. However, at present we know very little about how the integrin alphav beta8-TGF-beta pathway controls different types of immune response.The aim of this proposal is to identify a completely new way by which integrin alphav beta8 regulates immune responses. It was previously thought that this molecule is found on the surface of cells. However, we now find that the integrin is secreted from immune cells on so-called 'extracellular vesicles', which are known to be capable of promoting communication with other cells of the immune system. Our proposal will define the importance of this pathway, and how it is controlled. Such work will allow us to better understand the biological mechanisms that regulate the immune system to maintain health.