T Cell Biology

Group Head: Professor Barbara Fazekas de St Groth

The aim of the T Cell Biology Group is to use our knowledge of how T cell responses are controlled in order to design new therapies to prevent and/or treat diseases caused by dysregulated immune responses. We would like to be able to specifically target the immune attack in allergic, autoimmune and inflammatory disease without causing the non-specific immunosuppression that is a major side-effect of current therapies for these conditions. To do this, we will need to understand exactly how to intervene in dendritic cell, T cell and Treg cell (regulatory T cell) interactions to produce tolerance rather than an ongoing immune response.

Epidemiological studies have established that living under "hygienic" conditions is associated with a higher incidence of immune-mediated diseases, but the particular aspects of the "dirty" environment that exert a beneficial effect on the immune system have not yet been identified. If we find that deficiencies in Treg number and/or function are associated with the western epidemic of immune dysregulation, this will allow us to focus on those factors within the "dirty" environment that can increase Treg cell number and/or function. Our data regarding the factors that control the Treg network in mouse models will be crucial in guiding these studies.

We would also like to find new ways to enhance the immune response to cancer by inactivating Treg cells, as an adjuvant to established therapies.

Research focus

Diseases resulting from dysregulated immune responses are very common in the western world. The immune system causes the allergies that lead to asthma, hay fever, eczema and anaphylactic shock. It mounts the abnormal autoimmune attacks that manifest as diseases such as type 1 diabetes, thyroid disease, rheumatoid arthritis, multiple sclerosis and systemic lupus erythematosis. It produces digestive tract inflammation in coeliac disease, Crohn's disease and ulcerative colitis. It also plays a major role in driving the progression of pathology in atherosclerosis (vascular disease) and type 2 diabetes. Together, these diseases affect the majority of the population, and their chronic nature produces very significant health costs to the community. Not only are these diseases increasing in the western world, but they are starting to appear for the first time in developing nations.

The T Cell Biology Group's research is aimed at combating all these immune-mediated diseases, both through prevention and by developing new treatments. A dysfunctional immune response is a driving force in all these seemingly diverse conditions, so we are focussing on two key processes that control immune responses. The first is the interaction between CD4 T lymphocytes and dendritic cells. We are using mouse models in which the response of transgenic CD4 T lymphocytes can be programmed by different types of dendritic cells. These models are providing unique insights into the different functions of the many subtypes of dendritic cells, some of which drive immune responses while others prevent them. Our recent studies have defined several distinct subsets of dendritic cells in the skin, each with different behaviour and capacity to stimulate T cells.

The second major control on CD4 T lymphocyte responses is via a subset of T cells termed regulatory T cells (Tregs). Tregs are part of a crucial feedback loop that fine-tunes the strength of immune responses. Tregs are particularly effective in down-regulating low avidity responses such as those against self-antigens. Deficiencies in Treg cells in animal models predispose to the development of autoimmune and inflammatory disease, but also improve immune defence against cancer. Using mouse models, we are defining how Tregs are produced in the thymus, the factors that maintain their numbers in the periphery, and the mechanisms they use to down-regulate T cell responses. We have shown that Treg cells reduce the stimulatory capacity of dendritic cells by controlling expression of co-stimulatory molecules, and we are currently defining the molecular mechanism involved in this process.

With a view to translating these findings into the clinic, we are testing whether patients with inflammatory bowel disease and a number of autoimmune diseases including systemic lupus erythematosis and Sjogren's syndrome have deficiencies in Treg cells. In association with the Sydney Cancer Centre we are measuring the effect of chemotherapy on Treg and non-Treg cells, with a view to combining the anti-tumour effects of chemotherapy with therapeutic regimes that have maximum potency against Treg cells but spare the anti-tumour T cell response.

Finally, we are setting up studies to compare human Treg number and function in western versus developing countries, correlating the Treg data with the incidence of autoimmune, allergic and inflammatory diseases in each population.