T Cell Biology
Diseases caused by immune imbalances such as allergies and autoimmune diseases are on the rise. Immune imbalance may also be involved in many chronic health problems such as heart disease, obesity and diabetes.
Our laboratory team seeks to find the underlying causes of these immune imbalances and to work towards new treatments and preventions.
Group Head: Professor Barbara Fazekas de St Groth
Barbara Fazekas de St. Groth graduated in medicine with first class honours from the University of Sydney in 1981 and worked as a Professorial Intern and RMO at Royal Prince Alfred Hospital, Sydney before completing a PhD with JFAP Miller at the Walter and Eliza Hall Institute in Melbourne. She then undertook postdoctoral training with Mark Davis at Stanford University. She returned to Sydney in 1991 to set up a laboratory at the Centenary Institute of Cancer Medicine and Cell Biology. She was appointed Associate Professor in 2000 and Professor in 2007.
Her work is aimed at understanding how the immune system is regulated. In particular, she studies how dendritic cells and regulatory T cells control the activation and differentiation of CD4 T cells, using T cell receptor preclinical models and multiparameter flow cytometry. She has recently focused on the role of regulatory T cells in human disease. Together with colleagues at the Centre for Immunology in Sydney, she discovered a novel phenotyping strategy that allows pure populations of human regulatory T cells to be isolated and manipulated for use in the therapy of graft versus host disease and organ graft rejection, in addition to autoimmune disease and allergy.
T Cell Biology Group
Our approach is aimed at understanding the role of the immune system in chronic disease and, in particular, how immune imbalances can cause or exacerbate disease.
The number of people with autoimmune and allergic diseases, such as asthma, hay fever and type 1 diabetes, has more than doubled in the past 20 years. Such a rapid rise in these immune systemmediated diseases must have been caused by changes in environmental factors, because the frequencies of genes within populations take generations to change.” The T Cell Biology research group—which concentrates on the network managers of the immune system, T cells—aims to understand how the immune system usually prevents these diseases and which environmental factors are required to maintain normal immune function.
One of the theories that seek to explain this epidemic of immune disease is known as the hygiene hypothesis. This suggests that too much cleanliness in early life can cause disease because it reduces crucially important contact between the immune system and microorganisms.
Recent evidence points to the harmless microorganisms that populate our gut and skin, collectively termed the ‘human microbiome’, as an important regulator of immune function via a small but crucial population of T cells called regulatory T cells (T regs).
We are investigating how T regs influence immune function in humans and in animal models, particularly how they control the threshold of stimulation at which the immune system becomes activated.
Allergic reactions and autoimmune diseases arise when this threshold is set too low.
We have discovered a set of peacekeeper cells—immune cells in the outer layers of our skin that stop us from attacking friendly bacteria. Known as Langerhans cells, they have resisted every attempt by us to get them to generate an immune response. The work could open the way to new therapeutic options for immune-mediated diseases such as inflammatory bowel disease, of which Australia has some of the world’s highest rates.
But the immune system is a layered defence¬—and the next layer of skin has different kinds of immune cells, which program ongoing responses against bacteria. If bacteria penetrate deeply enough to meet these cells, the immune response will kill them.
The T Cell Biology research group has been using mice as models to investigate how T regs work.
Mice lacking T reg cells are particularly prone to autoimmune diseases and allergies. We have shown that this tendency can be reversed by administering T regs, and that the crucial effect of T reg administration is to control the levels of stimulatory molecules that trigger the immune system into action.
In a mouse asthma model, we have shown that administering T regs prevents allergic sensitisation. But once the mouse has an established allergy, T regs are no longer effective in stopping acute asthma attacks. In organ transplantation, T regs can prevent rejection but, once again, they must be administered before the organ graft is performed.
Conversely, T regs can hinder the natural immune response to tumours. We have shown that otherwise fatal tumours can be killed by T cells if the T regs are inactivated.
These animal studies have indicated that manipulation of T regs is likely to be more effective for prevention rather than treatment of immune system mediated disease.
To investigate the contribution of T reg abnormalities to human disease, we are pursuing two different approaches. First, the abnormalities in patients with a range of diseases, including inflammatory bowel disease, multiple sclerosis, Graves’ disease, psoriasis and lupus, are being studied in detail. Second, we are monitoring the differences in T regs between human populations living under conditions of high versus low incidence of autoimmune and allergic disease. By correlating these differences with changes in the microbiome in different environments, we will determine which microbiome components are important in maintaining resistance to immune-mediated diseases.
• Publishing a paper on Langerhans cells, the peacekeepers of the immune system, in the Proceedings of the National Academy of Sciences. This paper shows for the first time that some immune cells are pre-committed to stopping immune responses against friendly bacteria.
• Establishing a new mouse model to investigate the individual and combined contributions of the many different immune system cells (T cells, T regs, B cells, dendritic cells) to the natural anti-tumour response.
• Establishing the first initiative in the world to standardise T reg detection and analysis in clinical settings across multiple sites. This initiative is supported by the Transplantation Society of Australia and New Zealand (TSANZ) Tolerance Working group. It coordinates and teaches methods of conducting flow cytometry analysis of T regs, based on those discovered and used by Professor Barbara Fazekas de St Groth. T reg analysis is a new technology in the immune assessment of renal transplant patients.
• Beginning to study how ageing affects immune responses to influenza vaccination. Professor Barbara Fazekas de St Groth is part of a US consortium that received five years of National Institutes of Health/Broad Agency Announcement funding towards this project.