Our research has identified unprecedented communications between the microbes that colonize our body’s surfaces and killer T cell immunity. Our findings indicate that microflora is key to a healthy balance between two immune mediator systems that have opposing effect on T cell immunity. The project will extend our understanding of how this regulated and seeks to harness these novel insights to explain the well known, but poorly understood role of microbes in autoimmune diseases.
Lymphoid Organ Development: Synthetic Organogenesis Of Artificial Spleen And Characterisation Of Tissue-specific Hematopoiesis
Funder
National Health and Medical Research Council
Funding Amount
$350,232.00
Summary
Spleen is an organ which filters blood circulating around the body and provides immune protection against blood-borne pathogens. Research into spleen development will attempt to synthesise artificial spleen tissue, leading to possible tissue replacement therapies or enhancement of immunity towards infection or cancer. Cellular development in spleen will also be investigated with a view to identifying novel white blood cell subsets that have potential for becoming new targets for immunotherapy.
Discovery Early Career Researcher Award - Grant ID: DE170100398
Funder
Australian Research Council
Funding Amount
$410,507.00
Summary
How T cells modulate stem cells and tissue regeneration. The project aims to determine how T cells modulate tissue repair and regeneration in mammals. Most of the mechanisms modulating the healing of tissues are elusive. This research is expected to reveal unknown mechanisms controlling the processes of tissue repair and regeneration, particularly the nexus between the stem cells involved in the tissue healing process and the immune response .
The Role Of C-Cbl In The Regulation Of T Cell Signalling And Development
Funder
National Health and Medical Research Council
Funding Amount
$527,250.00
Summary
c-Cbl is a member of a multi-adaptor protein family that can interact with many signalling proteins via its different domains. Cbl proteins have been implicated as negative regulators of signalling pathways involving protein tyrosine kinases (PTKs). PTKs are enzymes which add phosphate groups to tyrosine residues on other protein substrates, and the process of tyrosine phosphorylation acts as a potent biochemical switch to turn signalling cascades on and off. Studies of Cbl-deficient (knockout) ....c-Cbl is a member of a multi-adaptor protein family that can interact with many signalling proteins via its different domains. Cbl proteins have been implicated as negative regulators of signalling pathways involving protein tyrosine kinases (PTKs). PTKs are enzymes which add phosphate groups to tyrosine residues on other protein substrates, and the process of tyrosine phosphorylation acts as a potent biochemical switch to turn signalling cascades on and off. Studies of Cbl-deficient (knockout) mice show that Cbl proteins are important in regulating the development of, and signalling by, cells of the immune system called T cells. c-Cbl knockout mice show greatly enhanced PTK-signalling responses and deregulated activity of a PTK called ZAP-70. The mechanism of this is not known, but analysis of a c-Cbl mutant mouse shows that this is not dependent on the tyrosine kinase binding (TKB) domain of c-Cbl. Therefore other functional domains of Cbl must be responsible for the increased signalling response in the c-Cbl knockout mouse. One candidate is the highly conserved RING finger domain which can modify Cbl-associated PTKs by addition of ubiquitin molecules. Ubiquitination of a protein often, but not always, leads to its degradation, and this could be how Cbl controls the strength and duration of signalling in T cells. However there may be other functions of the conserved RING finger yet to be identified. c-Cbl itself is prominently and very rapidly modified by tyrosine phosphorylation on tyrosine 737 by the Fyn PTK following T cell activation, but the role of this modification is not known and could also be essential for c-Cbl s function in T cells. We plan to investigate the roles of the RING finger domain and Fyn-mediated tyrosine phosphorylation in c-Cbl regulation of T cell signalling by analyzing knock-in mice that carry specific mutations disrupting the RING finger or tyrosine 737 in the c-Cbl gene.Read moreRead less
Systematically Exploring The Contribution Of Immunoproteasome To Immunodominance And T Cell Function
Funder
National Health and Medical Research Council
Funding Amount
$499,860.00
Summary
Vaccine will help us to fight both infectious diseases and malignancy. However, there are few successful vaccines for infectious agents and there is simply no vaccine to cure any tumor at the moment. So, it is essential for us to learn the basics related to vaccine development. Killer T cells eliminate tumour cells or virally infected host cells by recognising fragments (epitopes) derived from tumour- or virus-derived proteins displayed on a host molecule called MHC. Normally multiple epitopes a ....Vaccine will help us to fight both infectious diseases and malignancy. However, there are few successful vaccines for infectious agents and there is simply no vaccine to cure any tumor at the moment. So, it is essential for us to learn the basics related to vaccine development. Killer T cells eliminate tumour cells or virally infected host cells by recognising fragments (epitopes) derived from tumour- or virus-derived proteins displayed on a host molecule called MHC. Normally multiple epitopes are generated as part of the protein recycling program referred as proteine degradation which is mainly conducted by bundled enzyme complex, called proteasome. Two major forms of proteasomes are expressed by most cells. One called house-keeping proteasome and the other, which replaces the house-keeping one during viral infections is called immunoproteasome. The role that the immunoproteasome plays during anti-viral and anti-tumoral immune responses is not fully understood. In addition, the immunoproteasome is also expressed by a few cell types that do not suppose to need it if its function is entirely to generate better epitopes for MHC to display. In this project, we will sytematically explore the contribution of the immunoproteasome to overall anti-viral and anti-tumoral immune responses in three mouse model systems. The shared feature of these systems is that multiple killer T cell epitopes have been defined, which could potentially provide us with very sensitive assessments. The three systems are anti-influenza, anti-vaccinia virus and anti-tumor antigen (NY-ESO-1) mouse models.Read moreRead less
MAIT cells are a recently discovered type of lymphocyte that plays a unique and important role in the immune system. However, these cells vary widely in number between healthy individuals, for reasons that are unclear. This project is designed to understand the factors that control the development of MAIT cells as a step toward regulating their numbers and activity.
Role Of The CD8-Heparan Sulfate Interaction In CD8+ T Cell Development And Function
Funder
National Health and Medical Research Council
Funding Amount
$649,135.00
Summary
The immune system can recognise a large array of foreign pathogens without reacting to self-components. For this to occur T cells, the main mediators of immunity, must be made to tolerate self-molecules as they develop in the thymus. We have identified a novel interaction between a molecule called CD8 on T cells and a complex carbohydrate called heparan-sulfate, which helps auto-reactive T cells to be eliminates in the thymus. The aim of this project is to further investigate this phenomenon.
The Mechanisms Of Epithelial Cell Survival That Govern Thymus Function
Funder
National Health and Medical Research Council
Funding Amount
$620,967.00
Summary
The thymus is an organ dedicated to the production of crucial immune cells, called T lymphocytes. Cancer treatments, such as radiation or chemotherapy, destroy thymic function and impair immune recovery in patients. We aim to uncover molecular processes that govern the life and death decisions of cells in the thymus. Our goal is to then use this information to develop treatments to protect this critical organ from damage and improve immune recovery following radiation or chemotherapy.