Analysis of the effect of S mansomi infection on regulatory T cell development and function

Lead Research Organisation: University of Cambridge
Department Name: Pathology

Abstract

The immune response to antigen is regulated in a variety of ways including by regulatory T cells (T regs). An over exuberant immune response to antigen can be detrimental and could cause tissue damage. Following infection with a helminth such as S. mansoni there is good evidence to show that immune responses are dampened down. For example, it has been shown that allergic responses are diminished and also that autoimmunity, where the immune system destroys self tissue, is inhibited. We and others have shown that following exposure to S. mansoni antigens T regs are induced. NOD mice have been shown to have defects in T reg function and this might represent one of the predisposing features for development in autoimmunity. We find that following exposure to S. mansoni antigens there is an increase in T cell production of IL-10, a marker of T reg activity. Naturally arising and induced T regs have different functional characteristics and it is unclear whether the T regs induced by S. mansoni fall into both categories or only one of them. Regulatory T cells are known not oly to be induced by IL-10 but also TGFbeta both of which are elicited in the mammalian host by exposure to schistosomal antigens. We propose to characterise the T regs induced during infection with S. mansoni and exposure to schistosome antigens in normal mice and in NOD mice with their known defects in T reg activity. In this way we will be able to define not only the mechanisms by which this induction of T regs occurs but also have the potential to identify schistosome derived molecules mediating this effect. This could lead to the identification of novel biomodulators that might have potential in the treatment of inflammatory conditions such as autoimmunity and inflammatory bowel disease.

Technical Summary

Regulatory T cells (Tregs) have been shown to play a role in down regulating immune responses. Parasites such as S. mansoni have been shown not only to evade but also to utilise the mammalian host immune system to facilitate completion of their lifecycle and enable transmission to their secondary host, the snail. It has been proposed that the parasite induces the host to make TGFbeta which binds to TGFbeta receptor homologues on the schistosomula and the worm to facilitate their differentiation and maturation. This helminth, and antigens derived from it, also increase IL-10 production by a range of cell types including dendritic cells, B cells and T cells. We and others have evidence for the induction of T regs by S. mansoni antigens. These T regs might function to dampen down host immune responses to the parasite and inhibit tissue imunopathology. A secondary consequence of the induction of these T regs is that they influence the host response to other antigens including allergens and self antigens. The NOD mouse has a defect in T reg function and it therefore provides an ideal model to study the effects of S. mansoni on induction and function of T reg. We will therefore use the NoD mouse model in conjunction with normal mouse strains to establish how S. mansoni induces T reg activity. The availability of defined S. mansoni antigens which influence T reg development, the availability of a range of markers for T regs and functional assays in vitro and vivo will permit dissection of the pathways and cell interactions involved. This is a basic science application which uses defined model systems to address one of the ways in which host and parasite may have mutually co-adapted and evolved.

Publications

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Anne Cooke (Author) (2010) Importance of TLR2 in the direct response of T lymphocytes to Schistosoma mansoni antigens. in European journal of immunology

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Lehuen A (2010) Immune cell crosstalk in type 1 diabetes. in Nature reviews. Immunology

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Zaccone P (2006) Parasitic worms and inflammatory diseases. in Parasite immunology

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Zaccone P (2008) Interplay of parasite-driven immune responses and autoimmunity. in Trends in parasitology

 
Description This grant funding enabled us to demonstrate that exposure of NOD mice to soluble egg antigens (SEA) from the helminth S mansoni prevented development of Type 1 diabetes and that regulatory T cells (Treg) played a role in diabetes prevention.Diabetes prevention mediated by soluble worm antigens does not involve Treg activity.
Exploitation Route Identification of key biomodulators could lead novel reagents to prevent inflammatory disease. Identification of components within SEA that lead to Treg development could pave the way to the development of new biomodulators to inhibit inflammatory disease. It would be important to identify the pathways through which these biomodulators work as that would lead to the identification of druggable targets.
Sectors Healthcare

 
Description This study showed that there are several ways in which parasite antigens can modulate the immune response. This has implications for proposed therapeutic applications of parasite products for inflammatory disease.
First Year Of Impact 2009
Sector Healthcare