The regulation of protective immunity to viruses by L-selectin

动物和人类中的病毒感染引起病态和致命的疾病，这引起严重的经济负担。动物和人类对抗病毒的能力取决于一种称为T淋巴细胞的白色血细胞亚群。当病毒进入人体时，T淋巴细胞在局部淋巴腺中呈现病毒提取物，并在它们被派遣去对抗病毒之前转变为杀伤性T细胞。一些杀伤性T细胞变成记忆性T细胞，记忆病毒并防止再次感染。杀伤性T细胞如何找到病毒感染的组织，如流感感染的肺部，目前还不清楚。我们最新的工作已经确定了杀伤性T细胞上的归巢分子，称为L-选择素，它将它们引导到病毒感染的组织，并维持对该病毒的免疫记忆。L-选择素在T淋巴细胞转化为杀伤性T细胞时从T淋巴细胞表面丢失。所以在杀伤性T细胞离开淋巴腺之前，它们需要制造更多的病毒，否则它们就无法检测到体内的感染细胞。通过增加杀伤性T细胞上L-选择素的表达，我们可以增加感染部位的杀伤性T细胞的数量并增强对病毒的杀伤。然而，如果T淋巴细胞不产生更多的L-选择素，它们就无法定位病毒生长的位置并将其从体内清除。在这项提议中，我们想知道杀伤T细胞表面的L-选择素水平是如何控制的，以及L-选择素对记忆T细胞有什么影响。我们还将确定L-选择素如何通过找到与它结合的物质来感知病毒感染的组织，使T淋巴细胞进入病毒感染的器官。目前没有针对许多病毒的抗病毒药物，这些病毒在动物中引起显著的发病率，在年轻人和老年人中引起死亡率。此外，疫苗要么不可用，要么需要在每个季节重新配制，就像流感一样。我们对杀伤性T细胞归巢的研究揭示了一种增强免疫系统的新方法。这是通过增加杀伤性T细胞归巢到病毒感染的组织。了解L-选择素如何参与杀伤性T细胞将有助于开发新的方法来对抗人类和牲畜的病毒感染。

Virus infections in animals and humans cause morbid and fatal diseases which incur a severe economic burden. The ability of animals and humans to combat viruses depends on a subset of white blood cells called T lymphocytes. When a virus enters the body, T lymphocytes are presented with virus extracts in local lymph glands and turned into killer T cells before they are despatched to fight the virus. Some killer T cells turn into memory T cells which remember the virus and prevent re-infection. How killer T cells find their way to virus infected tissues, such as influenza infected lungs, is not understood.Our latest work has identified a homing molecule on killer T cells, called L-selectin, that directs them to virus-infected tissues and maintains immune memory to that virus. L-selectin is lost from the surface of T lymphocytes as they turn into killer T cells. So more of it needs to be made by the killer T-cells before they leave the lymph glands, otherwise they can't sense detect infected cells in the body. By increasing the expression of L-selectin on killer T cells we can increase the number of killer T cells at the site of infection and boost killing of virus. However, if T lymphocytes do not make more L-selectin they are unable to locate where virus is growing and clear it from the bodyIn this proposal we want to find out how the level of L-selectin on the surface of killer T cells is controlled and what effect L-selectin has on memory T cells. We will also identify how L-selectin senses a virus-infected tissue by finding what binds to it to make T-lymphocytes go to the virus infected organs. There are currently no anti-viral drugs for many of the viruses that cause significant morbidity in animals and mortality in young and elderly humans. Furthermore, vaccines are either not available or need to be re-formulated every season, like with influenza. Our studies of killer T cell homing have revealed a new way of boosting the immune system. This is by increasing the homing of killer T cells to virus infected tissues. Understanding how L-selectin is involved in killer T cells will help to develop new approaches to combat viral infections in people and livestock.