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.

About the T Cell Biology Group

The immune system is involved in many common chronic illnesses such as cancer, cardiovascular disease, infections, allergies and autoimmune diseases. 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. We are particularly interested in how increasingly rapid changes in the environment have increased the negative effects of the immune system on human health.

The T Cell Biology Group aims to understand how different parts of the immune system - CD4 T cells, dendritic cells and regulatory T cells - come together to determine whether an immune response will be beneficial or detrimental.Beneficial responses include defence against infection, particularly after vaccination, and long term control of cancer. Detrimental responses lead to the chronic inflammation present in cardiovascular and inflammatory bowel disease, asthma, type 1 diabetes, rheumatoid arthritis and multiple sclerosis. These inflammatory diseases are on the increase, and are believed to be due to lifestyle changes that have made the environment too "hygienic" to allow the immune system to function normally.

We are researching how interactions between the environment and the immune system can affect immune function. By comparing our results in preclincinal models and human studies, we hope to identify the environmental factors that interfere with normal immune function and lead to inflammatory disease. We are also researching methods to enhance long-term immune control of cancer.

Research focus

Human regulatory T cells
Following our landmark identification of CD127 as a key marker to distinguish between human activated versus regulatory T cells (Journal of Experimental Medicine 2006 vol 203 pp1693-1700 and 1701-11, together cited over 400 times since publication), we are now using this method to study human regulatory T cells in a number of conditions. This year we completed a study of patients undergoing chemotherapy for cancer at the Sydney Cancer Centre. In contrast to previous studies of early responses to chemotherapy, we showed that regulatory T cells are not selectively reduced over the course of multiple chemotherapy cycles.

In association with collaborators at Nepean Hospital, we have been defining the immune changes associated with pregnancy and have shown that the balance between regulatory T cells and pro-inflammatory Th17 cells is disturbed in pre-eclampsia, the most common serious complication in pregnancy.

We have recently collaborated with the Sydney Childhood Asthma Prevention Study to measure regulatory T cells in blood samples from a cohort of 150 eight-year-olds and to correlate our findings with clinical markers of allergic disease.

Dendritic cell function
The interaction between dendritic cells and CD4 T cells is fundamental in setting the course of the immune response. We are studying this in preclinical models to identify the functions of individual subtypes of dendritic cells, using the in vivo response of T cell receptor transgenic T cells as a readout. To date we have shown that epidermal Langerhans cells cannot support the generation of effector and memory CD4 T cells. This finding is important for understanding how dendritic cells at epithelial surfaces maintain tolerance to commensal organisms.

We have previously shown that dendritic cells over-express costimulatory molecules in immunodeficient models. We are testing whether the absence of regulatory T cells is specifically responsible for this phenotype. Our preliminary data indicate that regulatory T cells, but not conventional T cells, are able to reduce costimulatory molecule expression to normal levels.

We have also defined how T cells and dendritic cells interact to cause rejection of foreign grafts. Building on previous work showing that rejection of fully mismatched skin grafts is initiated within the graft itself and is not dependent on migration of dendritic cells from the graft to the host draining lymph node, we have now shown that rejection of pancreatic islet grafts also begins when cross-reactive primed T cells enter directly into the graft, liberating graft-derived antigen that recruits naïve T cells in the draining node, independent of dendritic cell migration.

In our asthma model, we are defining how regulatory T cells control the allergic response. We are currently testing whether regulatory T cell activation in vitro will enhance their ability to suppress lung inflammation.