Induction and maintenance of regulatory T cells and effector T cell hypo-responsiveness in chronic helminth infection

Lead Research Organisation: University of Edinburgh
Department Name: Sch of Biological Sciences

Abstract

Parasitic worms live within their human hosts for decades, and they do this by turning off the immune response. They use numerous tricks to this end, and the goal of our research is to identify their ploys in order to develop countermeasures. If an immune response is too vigorous it can cause damage while clearing the infection. To prevent this, one particular type of immune cell called a Regulatory T cell has the function of policing immune responses. We have found that worms are able to subvert this cell, using it to their own ends to dampen immune responses that would otherwise kill them. We are now investigating the mechanisms by which they subvert this cell. Understanding how worms turn off immunity is important at two levels; (1) to vaccinate or treat infection you need to be able to turn immunity back on, (2) strategies used by the parasite to switch off immunity can be applied to treat diseases caused by the immune system such as allergies, or to prevent rejection of organ transplants.

Technical Summary

Human helminth parasites cause chronic Th2-driving infections associated with long-term down-regulation of the host‘s immune responses. The key to protective immunity lies in the reversal of immune suppression, but how T cell responses are positively and negatively regulated during chronic infection is not well understood. Background: Using the murine model of filariasis Litomosoides sigmodontis I have demonstrated that filarial infection preferentially primes a Foxp3+ regulatory T (Tr) cell response that inhibits protective immunity. As infection develops, CD4+ T effector (Teff) cells up-regulate the co-inhibitory molecules CTLA-4 and PD-1 and become hypo-responsive resulting in a second level of immune regulation. I have shown that depletion of CD25+ Tr cells in combination with targeting co-stimulatory/inhibitory pathways will recover immune responsiveness and lead to protective immunity. Hypotheses: (1) A bias towards co-inhibitory signals, and/or a lack of co-stimulation, during infection favours the induction and maintenance of a Tr cell response and Teff cell hypo-responsiveness. (2) Manipulation of these pathways can be used to reverse immune regulation and induce protective immunity. Aims: (1) To determine how filarial infection preferentially induces a Tr cell response. (2) To determine how co-inhibitory/stimulatory pathways control Teff cell hypo-responsiveness and how they can be manipulated to induce protective immunity. (3) To determine whether therapeutic treatments developed using L. sigmodontis can be applied to treat other chronic helminth infections, e.g. Schistosoma mansoni. (4) To determine whether the regulatory elements that define susceptibility to filariasis in the mouse are also associated with parasite survival in the human filarial infection with Onchocerca volvulus. Design & methodology: We will manipulate co-stimulatory/inhibitory pathways in vivo using agonistic and blocking antibodies to test their role in Tr and Teff cell responsesuring L. sigmodontis and S. mansoni infection. Infections will be performed in IL-4gfp and Foxp3gfp reporter mice allowing us to track both Th2 Teff cells and Tr cells. This will be complemented with confocal immuno-fluorescence microscopy to visualise the priming and interactions of Tr and Teff cells during murine filarial infection, and to study Tr and Teff cells in onchocercomas (infection site) isolated from humans infected with O. volvulus. Scientific opportunities: As well as the development of therapeutic manipulations for the treatment of helminth infections, this work will provide fundamental insights into how Tr and Teff cells interact during infection and how T cell responses are regulated during a chronic Th2 immune challenge.

Publications

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Fulton A (2018) Use of the Litomosoides sigmodontis Infection Model of Filariasis to Study Type 2 Immunity. in Methods in molecular biology (Clifton, N.J.)

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McSorley HJ (2008) Expansion of Foxp3+ regulatory T cells in mice infected with the filarial parasite Brugia malayi. in Journal of immunology (Baltimore, Md. : 1950)

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Taylor MD (2007) CTLA-4 and CD4+ CD25+ regulatory T cells inhibit protective immunity to filarial parasites in vivo. in Journal of immunology (Baltimore, Md. : 1950)

 
Description Wellcome Trust ISSF
Amount £68,000 (GBP)
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 11/2012 
End 09/2014
 
Description Wellcome Trust ISSF
Amount £33,000 (GBP)
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 11/2012 
End 08/2013
 
Title Litomosoides regulation model 
Description Helminth parasites are able to subvert host immunity by turning off protective T cell responses resulting in chronic infections and an inability to generate protective immunity. We have functionally characterised regulatory and effector T cell responses during infection with the filarial helminth Litomosoides sigmodontis in mice. This model allows us to investigate the mechanisms by which helminth parasites suppress host immunity, and to test potential therapies that could be used to boost protective immunity in humans. 
Type Of Material Model of mechanisms or symptoms - mammalian in vivo 
Provided To Others? No  
Impact Using this model we have demonstrated a role for regulatory T cells in inhibiting host immunity during chronic helminth infections, and that protective immunity can be restored by manipulation of regulatory T cells. We have also developed strategies (targeting T cell co-stimulatory or co-inhibitory receptors) to enhance effector T cell responses, allowing them to overcome parasite-induced immune suppression and increasing host resistance to infection. 
 
Description Creation of inducible and constitutive IL-4Cre mice 
Organisation University of Manchester
Department Faculty of Life Sciences
Country United Kingdom 
Sector Academic/University 
PI Contribution Led the design and creation of the IL-4Cre and IL-4CreERT2 mice, and won funding from a Wellcome Trust ISSF award to make them. These mice will provide a valuable model for tracking and manipulating Th2 cell fate and investigating Th2 immune responses.
Collaborator Contribution Provided expertise on the creation of transgenic mice and designed the construct behind the IL-4 and IL-4CreERT2 mice.
Impact Have won a Wellcome Trust ISSF grant to pay for the creation of the mice. Expected completion Sep 2014.
Start Year 2010
 
Description Measuring changes in parasite fitness in response to therapeutic treatments 
Organisation National Museum of Natural History
Department Parisitology National Museum of Natural History
Country United States 
Sector Academic/University 
PI Contribution The experimental study was performed by my research team with training from our collaborator
Collaborator Contribution Staff training: morphological assessment of filarial parasites
Impact Publication: 19089814
Start Year 2007
 
Description Role of macrophage derived IL-10 in filarial infection 
Organisation University of Bonn
Department Institute of Medical Microbiology, Immunology and Parasitology
Country Germany 
Sector Academic/University 
PI Contribution Assisted with technical input to experiments, training of staff in immunological techniques, and intellectual input
Collaborator Contribution The study was organised and run by the collaborators. All financial aspects other than travel was covered by the collaborators.
Impact This collaboration resulted in a publication, Pubmed id: 21959021
 
Description Tregs in human Schistosomiasis 
Organisation University of Edinburgh
Department Institute of Immunology and Infection Research
Country United Kingdom 
Sector Academic/University 
PI Contribution Intellectual input into project design, and running of project
Collaborator Contribution Intellectual discussion
Impact A Wellcome Trust Project Grant to study regulatory T cells in human Schistoma infections
Start Year 2007
 
Description Wild Immunology 
Organisation University of Edinburgh
Department Institute of Evolutionary Biology
Country United Kingdom 
Sector Academic/University 
PI Contribution Provided immunological expertise and discussion.
Collaborator Contribution They have developed and run field studies on populations of wild mice, with a focus on the impact of infection and immune responses on survival and fitness.
Impact Wellcome Trust ISSF funding
Start Year 2011
 
Description Wild Immunology 
Organisation University of Glasgow
Department Institute of Biodiversity, Animal Health and Comparative Medicine
Country United Kingdom 
Sector Academic/University 
PI Contribution Provided immunological expertise and discussion.
Collaborator Contribution They have developed and run field studies on populations of wild mice, with a focus on the impact of infection and immune responses on survival and fitness.
Impact Wellcome Trust ISSF funding
Start Year 2011
 
Description School visit (Falkirk) 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? Yes
Type Of Presentation Keynote/Invited Speaker
Geographic Reach Local
Primary Audience Schools
Results and Impact Gave a talk to approximately 60 primary 7 (11-12 year olds) on my research into immune response to parasitic helminths, and how this relates to the treatment of allergies. Also gave an overview of how we go about scientific research, and a brief introduction into animals research

The kids enjoyed the presentation (particularly gruesome parasite pictures) and asked lots of questions. One came up to me at the end and said it was very interesting.
Year(s) Of Engagement Activity 2013