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

Lead Research Organisation: London Sch of Hygiene and Trop Medicine
Department Name: Infectious and Tropical Diseases

Abstract

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.

Technical Summary

IL-27 can both induce differentiation of Th-1 cells and limit T cell cytokine production, possibly via induction of IL-10. Using in vitro T cell priming models and in vivo infection and vaccination studies, we will test the hypothesis that IL-27 controls the expression of receptors of T cell activation (co-stimulatory receptors) and receptors of T cell regulation (regulatory receptors) to direct the T cell response. We will examine whether the interplay between IL-27 and positive co-stimulatory molecules leads to differentiation of Th-1 effectors and whether IL-27 signalling in combination with negative co-stimulation leads to differentiation of regulatory cells. Since IL-27R is also expressed memory CD4+ T cells it is possible that IL-27 signalling is required for long term persistence and/or reactivation of memory cells. Using infection and vaccination models, we will investigate the role of IL-27 in induction, persistence and reactivation of memory T cells and in resistance to challenge infection after vaccination. Although IL-27 can induce T cells to produce IL-10, the hypothesis that the regulatory activities of IL-27 are mediated by induction of IL-10 has not been formally tested. We will determine whether IL-27 and IL-10 independently control the activation of T cells, dendritic cells and macrophages during an inflammatory response to infection or whether IL-27 regulates cell function via induction of IL-10 (or vice versa). In the latter case, we will determine whether IL-10 is acting in an autocrine or paracine fashion. Lastly, we will ascertain the role of IL-27 during a severe and rapidly fatal infection in which pro-inflammatory T cell immunopathology is an essential component of the disease. We will test the hypothesis that the kinetics of the IL-27 response affect the size/activity of the initial Th-1 T cell response and/or the timing or magnitude of the subsequent regulatory T cell response.

Publications

10 25 50
 
Description We uncovered a previously unappreciated role for IL-27 in modulating CD4+ T cell chemotactic pathways during infection, which is related to its capacity to repress Th1 effector cell development. IL-27 appears to be a key cytokine that limits the CCR5-CCL4/CCL5 axis during inflammatory settings.
Exploitation Route IL-27 represents a pathway that can be modulated to regulate T cell trafficking in disease or immunotherapy
Sectors Healthcare,Pharmaceuticals and Medical Biotechnology

 
Description Dissecting the development and localisation of protective IL-10-secreting T cells in a model of hepatic immunopathology
Amount £485 (GBP)
Funding ID BB/I020950/1 
Organisation Biotechnology and Biological Sciences Research Council (BBSRC) 
Sector Public
Country United Kingdom
Start 03/2012 
End 09/2014
 
Description AMGEN 
Organisation Amgen Inc
Country United States 
Sector Private 
PI Contribution We analysed the response of WSX knock out mice to infection
Collaborator Contribution They provided a founder colony of WSX knock out mice
Impact Publications as listed
Start Year 2008
 
Description Hunter U Penn 
Organisation University of Pennsylvania
Department School of Veterinary Medicine (UPenn)
Country United States 
Sector Academic/University 
PI Contribution Generation of data and publication
Collaborator Contribution Intellectual contribution
Impact Numerous research publications with Professor C Hunter
Start Year 2011
 
Description The development and regulation of pathogenic T cell responses during malaria infection 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Participants in your research or patient groups
Results and Impact Research seminar, Strathclyde University

no actual impacts realised to date
Year(s) Of Engagement Activity 2011
 
Description The roles of IL-10 and IL-27 during experimental malaria infection 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Participants in your research or patient groups
Results and Impact Research seminar, University of Edinburgh, April 2010.

no actual impacts realised to date
Year(s) Of Engagement Activity 2010
URL http://www.parliamentlive.tv/Main/Archive.aspx
 
Description WSX-1: a critical regulator of pathogenic Th1 responses during malaria infection 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? Yes
Geographic Reach International
Primary Audience Participants in your research or patient groups
Results and Impact Invited seminar at Bernhard Nocht Institute for Tropical Medicine, Hamburg

no actual impacts realised to date
Year(s) Of Engagement Activity 2012