Mechanisms of Th2 cell-intrinsic hypo-responsiveness, and its impact on protective immunity and memory to parasitic helminths

Parasitic worms infect over 2 billion people worldwide resulting in huge health and economic burden. The parasites this proposal focuses on are filarial worms, which infect 120 million people, and can cause diseases such as elephantiasis and river blindness. They survive within humans for decades, and they do this using a variety of tricks to turn off the human immune responses that are responsible for killing infections. This poses a major barrier for vaccinations. Interestingly, this ability to switch off immunity also provides beneficial opportunities as some diseases (allergies, autoimmunity) are caused by unwanted or incorrect immune responses. This means we can harness the tricks parasites use to subdue immunity to treat allergies and autoimmunity.

The aim of this proposal is to identify how parasitic worms manipulate immune responses during infection. The central controller of immune responses is the T cell, and this cell-type is responsible for directing how immune responses clear infection. Although a strong immune response is required to kill parasites, if too strong it can cause damage at the same time. This means the immune system must finely balance how it deals with infection, responding just enough to kill the invader without causing injury. During chronic infection, when there is a greater chance of a sustained strong immune response causing damage, T cells can switch themselves off and become functionally inert. We find that this happens to the T cells responsible for killing helminths and as a consequence the parasite is not cleared. We are investigating the mechanisms by which T cells become inert during infection so that we can design vaccines or therapies able to switch T cells back on and clear infection. Alongside infection, unresponsive T cells are also a problem for treating cancers, whilst T cells that fail to switch-off cause allergies and autoimmune diseases. Thus, knowledge from this proposal can be applied to the development of treatments for cancers, autoimmunity, and allergies.

Helminth parasites infect over 2 billion people, representing a huge global disease burden. A key challenge to inducing protective immune memory lies in countering the dominant down-regulatory responses invoked during infection. We have demonstrated that CD4+ Th2 cells become intrinsically dysfunctional (hypo-responsive) during chronic helminth infection. This Th2 cell intrinsic hypo-responsiveness represents a novel form of anergy or exhaustion, is partially regulated by the PD-1/PD-L2 co-inhibitory pathway, and is a key element defining susceptibility to infection.

This aims of this proposal are to elucidate, (1) the mechanisms of Th2 cell hypo-responsiveness and in particular the roles of PD-1 and PD-L2, (2) whether it occurs during human helminth infection, (3) its impact on Th2 cell memory and vaccine efficacy, (4) how it may be countered therapeutically to restore protective immunity.

To address these aims I have developed the Litomosoides sigmodontis infection model of filariasis into a unique system for studying lymphocyte regulation during tissue nematode infection, and in particular for tracking and assessing the intrinsic functional quality of Th2 cells using IL-4gfp reporter mice. Novel mechanisms of hypo-responsiveness will be identified by gene array, and the PD-1/PD-L2 pathway elucidated using knock-out mice and chimaeras to restrict deficiencies to specific cell populations. We will relate Th2 cell hypo-responsiveness to human infection using gene expression data sets from filariasis patients, and stored PBMC samples from schistosomiasis patients.

In addition to the direct implications for the design of vaccines or treatments to promote protective memory to helminths, this study will have relevance well beyond helminth immunology. It will fundamentally enhance our knowledge of Th2 biology, and provide novel approaches for tolerising pathogenic Th2 cells for the treatment of Th2-mediated allergies and fibrosis.

The aim of this project is to develop a fundamental understanding of how Th2 responses are regulated during helminth infection, and in particular how Th2 cells are converted into a hypo-responsive or anergic-like state during chronic infection. This understanding will help define the checkpoints that determine whether a T cell remains inflammatory or becomes tolerised during chronic immune challenge, and will form the basis for the design of new immunological therapeutic strategies and vaccines that are able to: (1) counteract or prevent T cell-intrinsic tolerance and so promote effective protective immunity to infections and cancers. (2) Switch-off or tolerise pathogenic T cells to prevent damaging inflammatory responses such as allergies, fibrosis, or auto-immunity.

Health and well-being:
Helminth infections are responsible for huge morbidity worldwide (2 billion infected), and the design of therapeutics and vaccines to promote immunity to helminth infections will lead to improvements in the health of helminth-infected individuals. An improved understanding of how down-regulated chronic immune responses can be reawakened will also lead to new strategies for promoting immunity to tumors in cancer patients. Defining new strategies for alleviating pathogenic immune inflammatory responses by tolerising T cells will lead to treatments for patients with allergies and autoimmune diseases. The outcomes of this project will not lead directly to new treatments, but rather define new strategies and approaches for future testing. Thus, the timeframe for improvements to human health is predicted to be in the decades.

Commercial Sector and charities:
Identifying new approaches for reawakening 'tolerised' T cells, or tolerising pathogenic T cells will provide new directions for commercial exploitation. This has the potential to lead to spin-out companies to develop candidate drugs or immunological therapies, and could also benefit biotech and pharmaceutical companies, and charities with active biomedical research programs. This will lead to increased investment in Research and Development (2-5 years), and in the long-term (decades) could lead to the development of commercially exploitable drugs.

Policy:
Part of the proposal will identify how Th2 cell hypo-responsiveness impacts vaccine efficacies and formation of immune memory. This will have relevance for the timing and strategy for future anti-helminth vaccination programs, and potentially for current drug-treatment programs. Thus could impact the development of evidence-based international vaccine policies.