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Dr Gerard Hoyne

Senior Research Fellow - T cell development & regulation laboratory

Immunogenomics Group

Staff

Brief Biography

After studying as an undergraduate at the University of Western Australia, I completed my PhD in Microbiology at eh same Institution in 1992. I then undertook a postdoctoral fellowship in the Department of Biology at Imperial College of Science, Technology and Medicine in London with Professor Jonathan Lamb. It was here that I became interested in the possibility that developmentally regulated signalling pathways could be involved in cell fate determination in the peripheral immune system. In 1996 I was awarded the Pharmacia Research Fellowship for research into immune modulation in allergic diseases. In 1997 I moved to the University of Edinburgh and was appointed a Senior Research Fellow at the MRC Centre for Inflammation Research. During this time I continued to develop my interest on the role of the Notch signalling pathway in the induction of peripheral T cell tolerance. I also initiated studies on the role of the sonic hedgehog and Wnt signalling pathways in the control of T cell responses in the peripheral immune system. In 2002 I moved to The John Curtin School of Medical Research where I was appointed a Senior Research Fellow within the Division of Immunology and Genetics working with Professor Chris Goodnow. Currently we are using ENU mutagenesis to identify genes that protect individuals from autoimmune such as type 1 diabetes.

Contact Details

Immunogenomics Group
The John Curtin School of Medical Research
Building 54
The Australian National University
Canberra ACT 0200 Australia

T: +61 2 6125 2435
E: Gerard.Hoyne@anu.edu.au

Collaborators:
Dr Sally Dunwoodie VCCRI, Sydney, NSW
Dr Wally Langdon, UWA
Dr Sarah Russell, Peter Mac Cancer Institute, Victoria
Dr Sean Grimmond, University of Queensland
Dr Ed Bertram, JCSMR
Dr Cindy Guidos, University of Montreal

• Recent Publications
• Photos

Research Interests:

Genome wide mutagenesis screen to identify genes that regulate immune tolerance

Although we understand the cellular aspects of immune tolerance induction to self antigens (e.g. insulin) there is still a major gap in our knowledge of the genes and signaling pathways that control the fate of auto-reactive T cells in the body. To help breach these gaps we have embarked on a major program of work to identify new autoimmune gene variants using an ENU mutagenesis screen on a mouse model of organ-specific autoimmunity whereby defects in immune regulation can be identified by the development of type1 diabetes in mice. Currently we have identified 42 strains that have been confirmed to carry heritable mutations that lead to the development of type1 diabetes. Several of these strains are being characterized in detail to identify the mutation by genetic mapping as well as phenotypic analysis to identify how the mutation disrupts the checkpoints in T cell tolerance. We have also identified two strains that develop the non autoimmune disease Type2 diabetes which results from a metabolic disorder whereby muscle and fat cells are ‘resistant’ to the actions of insulin and compensatory mechanisms that are activated in the pancreatic b cell to secrete more insulin are not sufficient to maintain normal glucose homeostasis. These mice become obese at a young age and eventually become diabetic. Thus it is hoped we may gain further insight into the genes and signaling pathways that control the onset of Type2 diabetes.

The role of cbl proteins in regulation of T cell tolerance

T cell anergy is a process whereby the immune system is able to render autoreactive T cells functionally silent and one of the key genes that regulates this process is called cbl-b a ubiquitin ligase protein that targets antigen receptors and signalling proteins for degradation in the cell. In collaboration with Dr Wally Langdon (University of Western Australia) Eleanor Flening a PhD student in the group has been investigating the fate of autoreactive T cells in a mouse model of type1 diabetes which lack the cbl-b gene. She has shown that the process of thymic deletion of self-reactive T cells in the thymus is normal in cbl-b mutant mice, but these cells cannot be anergized in the peripheral lymphoid tissues. Thus the threshold of activation of cbl-b mutant T cells is greatly reduced which means that these can respond to extremely low levels of antigen which would not normally evoke a response from wild type cells. Thus we are beginning to gain a clear appreciation for the role cbl-b plays in the immune system to induce and maintain anergy in self-reactive T cells in the periphery. Exactly what are the targets of cbl-b in self-reactive T cells awaits further investigation. We are also investigating what role c-cbl, a protein highly related to cbl-b, has in regulating T cell tolerance in mice.

Splicing of CD45 is regulated by a novel splicing silencer protein

The cell surface marker CD45 was first described over 25 years ago and is critical for activation of T cells in the immune system in both mice and humans. It has long been recognized that the CD45 molecule undergoes splicing to remove three variable extracellular domains that is linked to the activation status of the T cell. Although there has been considerable research effort devoted to the CD45 molecule in the past two decades, surprisingly, there is still nothing known about the molecular mechanism that directs CD45 splicing. Importantly, dysregulation of CD45 splicing has been linked to autoimmune disease susceptibility in particular multiple sclerosis in human patients. We have identified a novel mouse strain through the ENU mutagenesis program that has a selective defect in splicing of CD45 on T cells that leads to a loss of T cells in the peripheral blood and immune tissues. Zuopeng Wu a PhD student in the lab has mapped the mutation to a small region on mouse chromosome 17 that happens to contain a cluster of genes associated with alternative splicing and one of these is a nuclear protein known to be involved in mRNA splicing. In collaboration with Dr Ed Bertram and his PhD student Daniel Shehan we plan to investigate how dysregulation of CD45 splicing affects T cell responses to viral antigens and also disease susceptibility in a mouse model of multiple sclerosis. We are collaborating with Sean Grimmond at the University of Queensland to use a microarray approach to identify the global array of targets of the splicing regulator gene we have identified. This strain is likely to provide some novel insights into the function and splicing of the CD45 molecule on T cells and its role in promoting autoimmune disease susceptibility.

Regulation of Notch signalling in T cell development and function:

Notch signalling is critical for T cell development that is mediated through binding of the Notch receptor expressed on thymocytes to its ligand Delta expressed on the surface of thymic epithelial cells. Recent studies have shown that thymocytes must continually engage the Notch receptor throughout their development in the thymus, but Notch signalling must also be silenced at a particular stage of T cell development. Dysregulation of Notch signalling in thymocytes can lead to the development of T cell leukaemia. Exactly how thymocytes tune down the Notch receptor during their development is not known. In collaboration with Gavin Chapman and Sally Dunwoodie (Victor Chang Cardiac Research Institute, Sydney) we have identified that the Delta3 ligand functions in a completely distinct manner to the other Delta ligands, Delta1 and Delta4. These latter two ligands are normally expressed on one cell and can bind to the Notch receptor on an adjacent cell to activate signalling which is referred to as trans-activation. In contrast, the Delta3 cannot bind Notch in trans- to activate signalling, but instead the Delta3 ligand is usually expressed on the same cell as the Notch receptor and as a result can bind to Notch in cis- to inhibit signalling. The loss of Delta3 expression in thymocytes leads to augmented Notch signalling and enhanced T cell production. This is the first reported function for cis-inhibition of Notch signaling in the immune system and may help us understand how this pathway coordinates cell survival and differentiation in the thymus. Until now most interest of Notch signalling in the thymus has focused on its role in the early events of T cell lineage commitment. However, we would like to know what role Notch signaling may play during negative selection of autoreactive T cells. We will use a transgenic model to study negative selection of antigen-specific T cells and will investigate using both gain of function and loss of function approaches to determine what effect enhancement or loss of Notch signaling has on the fate of autoreactive T cells in vivo. We have previously identified an ENU mouse variant that carries a mutation in a transcription factor Ikaros which is critical for T cell development and these mice exclusively develop T cell leukaemias. In recent years there has been evidence to suggest that Ikaros can act in normal thymocytes to repress Notch signalling at a particular stage of T cell development. Exactly how Ikaros and Notch cooperate to drive T cell leukaemia is not understood and Yovina Sontani a PhD student in the lab is addressing this problem. She has been performing a detailed analysis of T cell development the Ikaros mutant mice and has identified that the predilection to develop leukaemia is associated with the ‘loss of heterozygosity’ of the remaining wild type Ikaros allele. We are also studying the relationship between Ikaros and Notch signalling in pre-leukeamic and leukaemic cells to determine if Ikaros functions to normally repress Notch signalling in thymocytes. We have available a number of different mouse strains with mutations in various components of TCR signal transduction and using both in vivo and in vitro assays we are investigating how Notch an affect TCR signals during development to direct T cell differentiation