Mechanisms Regulating The Shutdown Of Cytotoxic T Cell Populations In Acute And Persistent Viral Infections
Funder
National Health and Medical Research Council
Funding Amount
$386,120.00
Summary
Apoptosis, or programmed cell death, is the form of cell death responsible for removal of unwanted or excess cells from the body. This is an essential mechanism to allow remodelling of tissues as an embryo grows and is a crucial way in which the body prevents the unwanted outgrowth of individual cell types. Control of cell growth in this way is a key checkpoint in preventing cancers. This regulatory mechanism is also important in determining the number and type of immune cells that are generated ....Apoptosis, or programmed cell death, is the form of cell death responsible for removal of unwanted or excess cells from the body. This is an essential mechanism to allow remodelling of tissues as an embryo grows and is a crucial way in which the body prevents the unwanted outgrowth of individual cell types. Control of cell growth in this way is a key checkpoint in preventing cancers. This regulatory mechanism is also important in determining the number and type of immune cells that are generated at steady state and following an immune response. Two families of proteins are essential in initiating this process of apoptosis. One is known as the BH-3-only family, while the other is the tumour-necrosis receptor (TNFR) family. These families are made up of several family members, each of which responds to different types of stimuli, and are expressed in different tissues in the body. So far only one BH-3-only family member, BIM, has been identified to regulate shut-down of an immune response. This action prevents the generation of large numbers of highly aggressive cells that are specific for a pathogen inadvertently causing damage to the body. This control checkpoint is a normal, but vital, part of the immune response. Other members of these families are also likely to play an important role in this process, but as yet their identity is unknown. This study will determine which members of the BH-3-only and TNFR family members play a role in (i) regulating the numbers of lymphocytes present at steady state, and (ii) in the shut-down process in different types of pathogen infection. This work will provide insight into how lymphocytes are regulated in the resting animal, and in disease.Read moreRead less
Investigating The Delivery Of Cytotoxic T Cell Lytic Granules And The Microenvironment Of The Immunological Synapse
Funder
National Health and Medical Research Council
Funding Amount
$355,169.00
Summary
T cells recognise infected or cancer cells and eliminate them from the body. They kill their targets by tightly attaching and releasing toxic proteins, which cause the target to undergo cell suicide. This research will use high resolution imaging to investigate the environment of the synapse between the two cells and understand parameters required for the delivery of a lethal hit. This will provide powerful insights into the working of the cell, and may identify novel intervention targets
Analysis Of The Molecular Functions Of Perforin: A Critical Role In Tumor Immunosurveillance
Funder
National Health and Medical Research Council
Funding Amount
$318,916.00
Summary
Over the past decade, great steps have been made in defining the key molecules used by killer cells of the immune system that eliminate cancerous- and virus-infected cells and many of these advances have originated in our laboratory. It is now clear that granule-mediated cytolysis is a key mechanism for controlling both primary and metastatic cancers in transplanted syngeneic, allogeneic and xenogeneic tumor models in mice. The pore-forming protein, perforin is indispensable for effective killer ....Over the past decade, great steps have been made in defining the key molecules used by killer cells of the immune system that eliminate cancerous- and virus-infected cells and many of these advances have originated in our laboratory. It is now clear that granule-mediated cytolysis is a key mechanism for controlling both primary and metastatic cancers in transplanted syngeneic, allogeneic and xenogeneic tumor models in mice. The pore-forming protein, perforin is indispensable for effective killer cell function in these models. But the role for perforin expressing killer cells in tumor surveillance against spontaneous tumorigenesis is still hotly debated. Our proposal to study tumor development in perforin-deficient p53-mutant tumor prone mice will enable us to answer this question. Furthermore, the molecular mechanisms by which perforin functions are poorly understood. We therefore also propose to complete a structure-function analysis of perforin using unique tools and information that our laboratory has at its disposal. The long-term goal will be to better understand the function of perforin at the molecular level such that the rationale design of therapeutic perforin inhibitors may become a reality for future regulation of killer cell effector functions in disease.Read moreRead less
Identifying Novel Regulators Of RNA Receptor Signalling To Modulate Viral Innate Immunity
Funder
National Health and Medical Research Council
Funding Amount
$312,034.00
Summary
Viruses elicit a rapid immune response upon infection that is crucial for controlling viral spread and disease. Human cells detect viral molecules to coordinate the the production of anti-viral proteins. The aim of this research is to identify new genes that are essential for controlling the initial immune response to viral infection. This research will help us understand how virus infection can be controlled appropriately, and may lead to the development of new anti-viral therapeutics.
Investigation Of The Roles Of TNFa-related Apoptosis-inducing Ligand, TRAIL, In The Immune System.
Funder
National Health and Medical Research Council
Funding Amount
$436,980.00
Summary
TRAIL, is a newly described member of the tumour necrosis factor (TNF)-family of cytokines, which can kill a wide range of tumour cells, and virus infected cells, but not most normal cells. TRAIL has proven to be safe when administered to normal, tumour bearing, and virally-infected mice, and causes no detectable side-effects in these animals. As such it holds huge potential and is being widely investigated for use as a new anti-cancer therapy. Despite these findings, little is known about the t ....TRAIL, is a newly described member of the tumour necrosis factor (TNF)-family of cytokines, which can kill a wide range of tumour cells, and virus infected cells, but not most normal cells. TRAIL has proven to be safe when administered to normal, tumour bearing, and virally-infected mice, and causes no detectable side-effects in these animals. As such it holds huge potential and is being widely investigated for use as a new anti-cancer therapy. Despite these findings, little is known about the true physiological role of TRAIL in vivo. To define the normal roles of TRAIL, CIA has been characterising TRAIL gene knock-out mice. These studies have confirmed that TRAIL contributes to control of tumours in vivo, and in early events during anti-viral responses. However, these studies have also revealed novel roles for TRAIL in T cell biology, and B cell memory. Understanding how TRAIL contributes to these processes, will shed significant light on the potential of TRAIL to be used as a therapeutic agent for humans with lymphoproliferative disease, for illiciting better long-lived antibody responses such as after vaccination, and as an anti-viral reagent in immunocompromised individuals during virus infection.Read moreRead less