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

免疫系统必须迅速动员起来以消除感染，但要严格调节以防止自我伤害的免疫反应。当这种调节机制失效时，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性疾病（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许多不同的细胞相互沟通，我们必须了解这种沟通中涉及的信号和机制，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是由一种称为转化生长因子-β（TGF-β）的蛋白质提供的。TGF-β是一种抗炎分子，在调节潜在有害的免疫反应中很重要。然而，在某些情况下，TGF-β能够促进有害的免疫反应。因此，了解这个关键分子是如何控制的，对于了解免疫系统是如何正确调节的至关重要。我们最近的工作突出了一个重要的途径，这是至关重要的控制行动的TGF-β在免疫系统中。因此，我们已经证明，一种称为整合素α v β 8的受体，当存在于称为树突状细胞的免疫系统细胞上时，激活TGF-β以抑制肠道中的有害免疫反应。此外，该途径在自身免疫和感染模型期间促进有害的免疫应答中是重要的。因此，整合素α v β 8在控制多种免疫反应中至关重要。然而，目前我们对整合素α v β 8-TGF-β通路如何控制不同类型的免疫应答知之甚少，本提案的目的是确定整合素α v β 8调节免疫应答的全新方式。以前认为这种分子存在于细胞表面。然而，我们现在发现，整合素是从免疫细胞分泌的所谓的“细胞外囊泡”，这是已知的能够促进与免疫系统的其他细胞的通信。我们的建议将定义这一途径的重要性，以及如何控制它。这项工作将使我们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.