• Overview

Overview of our research

The orchestration of a successful immune response requires a tight balance between mobilising a sufficient and correct effector response, whilst simultaneously regulating that response to prevent it becoming pathogenic. Helminth parasites excel at subverting this balance, using the host’s own immune regulatory mechanisms to prevent effective immunity, resulting in immune suppression and chronic infection in the majority of individuals.

Aims:

The goals of my research are to use murine models of helminth infection to define how T cell responses are positively and negatively regulated during chronic infection. We aim to use this knowledge to develop therapeutic interventions that manipulate the regulatory/effector balance to either restore protective immunity to infections, or dampen the pathogenic immune responses that cause allergies or autoimmune diseases.

Background:

The main focus of our research exploits the ability of the filarial parasite, Litomosoides sigmodontis, to develop a fully patent infection within inbred mouse strains. We have developed this model of filariasis into a unique system for studying Foxp3+ regulatory T (Treg) and Th2 cell biology during infection, leading to the key observation that two levels of T cell regulation control susceptibility to filarial infection:

  1. Filarial parasites rapidly and preferentially recruit/induce suppressive CD4+Foxp3+ Treg cells.
  2. CD4+ Th2 cells become imprinted with an intrinsically dysfunctional (hypo-responsive) phenotype as infection progresses, with resemblance to adaptive tolerance or exhaustion.

We also employ murine models of gastro-intestinal helminths (Heligmosomoides polygyrus) and schistosomiasis (Schistosoma mansoni) as a complement to our work on filariasis.

Our Current Research:

Foxp3+ Regulatory T cells

We have shown that Foxp3+ Tregs respond remarkably rapidly to filarial parasites, faster than Th2 cells, resulting in a preferential expansion and early bias towards Foxp3+ Tregs (Taylor et al. Eur. J. Immunol. 39: 192 – 206). These CD25+Foxp3+ Treg cells inhibit protective immunity, and we’ve demonstrated that targeting Foxp3+ Tregs is a potential therapeutic strategy for enhancing immunity (Taylor et al. J. Immunol. 174: 4924 – 4933; Taylor et al. J. Immunol. 179: 4262 – 4634). We’ve also shown that ICOS plays an important role in the development of Foxp3+ Treg responses to helminths (Redpath et al. Eur. J. Immunol. 43: 705 – 715).

We are currently working to elucidate the relative roles of thymic (natural) versus peripheral (adaptive) Foxp3+ Treg cells during infection, as well as identifying the factors responsible for initiating and maintaining Foxp3+ Treg cells. We’re also interested in whether helminth infection results in the generation of Foxp3+ Treg memory cells.

Th2 cell-intrinsic hypo-responsiveness

We have demonstrated that CD4+ Th2 cells become intrinsically dysfunctional (hypo-responsive) during chronic helminth infection (van der Werf et al. PLoS Pathog. 9:e1003215). This Th2 cell-intrinsic hypo-responsiveness represents a novel form of anergy or exhaustion, involves the PD-1/PD-L2 co-inhibitory pathway, and its development is a key element defining susceptibility to infection. By blocking PD-1 or PD-L2 we can partially reverse hypo-responsiveness and enhance protective immunity. We’ve also demonstrated that we can enhance Th2 cell functional quality by providing super-physiological GITR co-stimulation (van der Werf et al. J. Immunol. 187: 1411 – 1420), and can promote resistance to infection by blocking the co-inhibitor CTLA-4 (Taylor et al. J. Immunol. 179: 4262 – 4634).

Our current focus is to identify the mechanisms of Th2 cell-intrinsic hypo-responsiveness, and to further elucidate the role of the PD-1/PD-L2 pathway. We are also working to identify the cell types responsible for conditioning Th2 cells towards hypo-responsiveness, as well as defining its impact on vaccination and the development of Th2 cell memory. Our overall goal is to be able to therapeutically manipulate T cell quality to switch them between active and inactive (tolerised) states. In this way we hope to counter Th2 cell dysfunction during helminth infections to promote protective immunity, and to develop new approaches for tolerising activated pathogenic Th2 cells that cause allergic disease and types of fibrosis.