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

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.

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 responses during 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.