IL-27: a regulator of T cell priming differentiation and memory during infection and vaccination?

疫苗接种是控制传染病的最具成本效益和可持续的手段，它取决于在疫苗接种过程中形成的杀死入侵微生物的机制可以在感染时迅速重新激活这一原则。然而，许多感染的一个共同特征是，消除传染性生物体所必需的免疫机制也可能导致组织损伤，从而导致疾病的体征和症状。对于那些由强有力的炎症机制控制的感染尤其如此——炎症是将免疫细胞带到感染部位所必需的，但副作用是肿胀、疼痛和组织损伤。当感染发生在关键器官系统（如肺、肝、脑）时，与炎症相关的损害可导致非常严重的疾病或死亡。因此，许多与感染相关的疾病实际上是由我们试图对抗感染的免疫反应引起的，而且还有一种危险，即某些形式的疫苗接种也可能在不经意间导致严重的副作用，当接种疫苗的个体随后被感染时。事实上，有几个实验疫苗不得不放弃的例子，因为接种疫苗的人感染后会伴有严重的疾病。为了控制感染而不引起严重疾病，需要非常小心地控制炎症免疫反应。理想情况下，炎症只会持续到感染得到控制，然后在广泛的组织损伤发生之前迅速停止。过早关闭炎症反应可能会阻止病原体被杀死，这最终也会导致严重的疾病，因为微生物会直接损害和破坏身体的基本组织。因此，开关信号的时间和强度可以决定感染的结果。这种关闭发生的一种方式是（通过免疫系统的“调节”臂）产生抗炎信使（抗炎细胞因子）。然而，越来越清楚的是，除了专门的抗炎细胞因子外，一些其他细胞因子可以根据特定情况具有促炎或抗炎特性。重要的是，尽管这种功能上的“转换”对炎症的调节至关重要，但我们仍然对这些细胞因子如何或在什么情况下从促炎变为抗炎知之甚少。最近发现的细胞因子IL-27就是这样一种细胞因子，已被证明具有相反的促炎和抗炎作用。在这个项目中，我们计划测试IL-27代表调节免疫反应的基本开关的假设，我们计划了解这种情况发生的机制。我们将使用一种实验系统，让正常小鼠或经过基因改造不能产生IL-27的小鼠感染一种寄生虫（疟原虫，在人类中引起疟疾）或接种一种实验性疫苗以预防疟原虫感染，研究IL-27（或缺乏IL-27）对免疫反应初始诱导的影响。小鼠在一段时间内维持这种免疫反应（免疫记忆）的能力，以及它们通过转换为抗炎反应来调节炎症反应的能力。如果我们的假设是正确的，我们的工作应该为疫苗开发人员提供新的工具（测量IL-27及其影响）来评估其疫苗的有效性和安全性。我们的工作也可能有助于开发新的药物来控制急性或慢性炎症。

Vaccination offers the most cost-effective and sustainable means to control infectious diseases and depends upon the principle that mechanisms for killing the invading microbe - which develop during the vaccination process - can be rapidly reactivated upon infection. However, a common feature of many infections is that the immune mechanisms that are essential to eliminate the infectious organisms can also cause tissue damage and thus contribute to the signs and symptoms of disease. This is especially true for infections which are controlled by potent inflammatory mechanisms - inflammation is required to bring immune cells to the site of infection but the side effects are swelling, pain and tissue damage. When infection occurs in critical organ systems (e.g. lung, liver, brain) the damage associated with inflammation can cause very severe disease or death. Thus, much of the illness that is associated with infection is actually caused by the immune response that we make to try to combat the infection and there is also a danger that some forms of vaccination may also, inadvertently, lead to serious side effects when the vaccinated individual is subsequently infected. Indeed, there are several examples of experimental vaccines that have had to be abandoned because of the severe disease that accompanied infection in vaccinated individuals. In order to control infection without causing severe disease, the inflammatory immune response needs to be very carefully controlled. Ideally, the inflammation proceeds only until the infection is brought under control and then is quickly switched off before extensive tissue damage occurs. Switching off the inflammatory response too early may prevent the pathogens being killed and this will also, in the end, result in severe disease as the microbes directly damage and destroy essential tissues of the body. Consequently the timing as well as strength of the switching signal can determine the outcome of infection. One way in which this switching off occurs is by production (by the 'regulatory' arm of the immune system) of anti-inflammatory messengers (anti-inflammatory cytokines). However, it is becoming clear that in addition to specialised anti-inflammatory cytokines, some other cytokines can have either pro- or anti-inflammatory properties depending upon the particular circumstances. Importantly, although this 'switch' in function is critical for the moderation of inflammation, we still have a very poor understanding of how or under what circumstances these cytokines change from being pro-inflammatory to anti-inflammatory. The recently discovered cytokine IL-27 is one such cytokine that has been shown to have opposing pro-inflammatory and anti-inflammatory effects. In this project we plan to test the hypothesis that IL-27 represents an essential switch that enables modulation of the immune response and we plan to understand the mechanisms by which this occurs. Using an experimental system in which normal mice, or mice genetically engineered to be unable to make IL-27, are either infected with a parasite (Plasmodium species, that in humans cause malaria) or vaccinated with an experimental vaccine to protect against Plasmodium infection, we will examine the effect of IL-27 (or the lack of IL-27) on the initial induction of the immune response, on the ability of mice to maintain this immune response over time (immune memory) and on their ability to regulate inflammatory responses by switching to an anti-inflammatory response. If our hypotheses are correct, our work should provide vaccine developers with new tools (measurement of IL-27 and its effects) to assess the efficacy and safety of their vaccines. Our work may also help in the development of new drugs to control acute or chronic inflammation.