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

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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.