Molecular Interactions Of The Tetraspanins CD37, TSSC6 And CD151 In T Cells
Funder
National Health and Medical Research Council
Funding Amount
$566,575.00
Summary
The tetraspanins are a new type of protein that are found at the surface of cells. Cells of the immune system, such as white blood cells, display at their surface, up to 20 different tetraspanin proteins. However, the precise contributions of these tetraspanin proteins to immunity is still not clear, nor is it clear exactly how tetraspanin proteins differ from one another and why white blood cells need to display so many different tetraspanins. Using genetic technology we have created mice which ....The tetraspanins are a new type of protein that are found at the surface of cells. Cells of the immune system, such as white blood cells, display at their surface, up to 20 different tetraspanin proteins. However, the precise contributions of these tetraspanin proteins to immunity is still not clear, nor is it clear exactly how tetraspanin proteins differ from one another and why white blood cells need to display so many different tetraspanins. Using genetic technology we have created mice which are unable to express certain individual tetraspanin proteins at their cell surface. Excitingly, the immune systems of these mice are not normal, in particular one type of white blood cell, the T cell responds in an exaggerated manner to stimulation. These results suggest a role for tetraspanins in the control and regulation of the immune system. This project will extend these results and work out the precise molecular mechanism by which the tetraspanins exert this control. In the future, a full understanding of how tetraspanins control T cells may ultimately lead to novel ways of controlling the immune system.Read moreRead less
Structural Basis Of Influenza A Virus-specific CD8+ T Cell Receptor Diversity
Funder
National Health and Medical Research Council
Funding Amount
$469,500.00
Summary
Viral infection results in the activation and proliferation of virus-specific T cells that mediate clearance of virally infected cells. Recognition of virally infected cells is meditated by presentation of peptide fragments complexed to Major histocompatibility complex (MHC) class I glycoproteins. Virus-specific T cells recognise these viral protein fragments via a specific receptor expressed at the T cell surface. This proposal plans to examine the structural factors that determine influenza-sp ....Viral infection results in the activation and proliferation of virus-specific T cells that mediate clearance of virally infected cells. Recognition of virally infected cells is meditated by presentation of peptide fragments complexed to Major histocompatibility complex (MHC) class I glycoproteins. Virus-specific T cells recognise these viral protein fragments via a specific receptor expressed at the T cell surface. This proposal plans to examine the structural factors that determine influenza-specific T cell receptor recognition. From these studies, we plan to determine how these structural factors can influence the diversity of virus-specific T cells that are generated after viral infection. The conclusions from these studies will enable us to determine why some virus-specific T cell responses are not diverse and what are the consequences for virus-specific T cell immunity. This has implications for the development of novel vaccine strategies designed to induce immunity against both viral and tumour challenge.Read moreRead less
Role Of Plasmacytoid Dendritic Cells And Neutrophils In The Generation Of Antiviral Immunity
Funder
National Health and Medical Research Council
Funding Amount
$469,500.00
Summary
Work described in this application is important in understanding how two very different types of white blood cells, namely neutrophils and plasmacytoid dendritic cells (PDC), contribute to the generation of an effective immune response and control of virus growth. Both these cell types are activated in the earliest phase of the host response and are likely to play crucial roles in determining the nature of the later components of the response. We have recently shown that animals depleted of Gr-1 ....Work described in this application is important in understanding how two very different types of white blood cells, namely neutrophils and plasmacytoid dendritic cells (PDC), contribute to the generation of an effective immune response and control of virus growth. Both these cell types are activated in the earliest phase of the host response and are likely to play crucial roles in determining the nature of the later components of the response. We have recently shown that animals depleted of Gr-1+ cells, with monoclonal antibody (mAb) RB6-8C5, rapidly succumb to a poxvirus infection (mousepox) with 100% mortality. In contrast, mice treated with a control mAb clear the infection very effectively. Host responses essential for recovery from mousepox, including antiviral cytotoxic T lymphocyte (CTL) response and gamma interferon production, are severely diminished in mice treated with the Gr-1+ cell depleting mAb. Since the mAb can potentially deplete both neutrophils and PDC, this raises the important question of whether one or both of these cell types may be involved in the generation of cytokine and cell-mediated immune responses to viral infection. Although PDC and neutrophils themselves are not thought to present antigen to T cells, the elucidation of how they may control the generation of this major arm of the immune response will be novel and has important implications for vaccine design. Virtually nothing is known about how neutrophils or PDC influence viral antigen presentation by antigen presenting cells. Several murine models of viral infection, that in many ways mimic the diseases in humans, will be used to map the sequence of events initiated by PDC and neutrophils and which end in the clearance of virus from the host. Understanding these pathways and identifying the essential mediators and their interactions is critical in elucidating the role of the two cell types in the host response to virus infection.Read moreRead less
The establishment of an immune system that is able to distinguish between self and non-self is of fundamental importance for good health and survival. How this specificity is achieved has been an area of intense investigation for many years because a breakdown of this process leads to the development of autoimmune diseases, such as diabetes, or an inability to fight pathogenic organisms. It has been known for many years that the development T cells, a subset of cells involved in mounting immune ....The establishment of an immune system that is able to distinguish between self and non-self is of fundamental importance for good health and survival. How this specificity is achieved has been an area of intense investigation for many years because a breakdown of this process leads to the development of autoimmune diseases, such as diabetes, or an inability to fight pathogenic organisms. It has been known for many years that the development T cells, a subset of cells involved in mounting immune responses, occurs in the thymus. The thymus produces large numbers of immature T cells (called thymocytes) from which a small number receive the appropriate signals to survive and develop into mature T cells. These tailor-made T cells can then enter the blood and peripheral lymphoid organs where they fight infectious organisms without reacting against host (i.e. self) tissues. The work for this project is aimed at determining how proteins inside thymocytes transmit signals that determine whether thymocytes either survive, and develop into T cells, or are eliminated because they react too strongly with self proteins. We have established that a protein called c-Cbl is central to this process as it regulates the initial strength of the signal that determines the fate of thymocytes. Our aim is to identify the putative key protein regulated by c-Cbl that can sense when a signal is too strong following the binding of a thymocyte to a self protein and directs a cell death signalling response. From this critical point of signal splitting we also aim to identify proteins that relay the death signal to the nucleus where they trigger the production of well-characterised proteins required to mediate cell death. By identifying the proteins in this signalling pathway we will have a greater capacity to control the magnitude of immune responses and therefore be able to lessen tissue damage caused by autoimmune reactions.Read moreRead less
Imaging the generation and recall of protective antiviral immune responses in vivo. Our understanding of the in vivo dynamics of cellular immune responses to infectious diseases is poor. This project will utilise advanced intravital imaging combined with novel tools to dissect the cellular events involved in the generation and recall of T cell responses to localised virus infection, combined with a detailed functional analysis of the lymphoid organ stroma. Such fundamental information will contr ....Imaging the generation and recall of protective antiviral immune responses in vivo. Our understanding of the in vivo dynamics of cellular immune responses to infectious diseases is poor. This project will utilise advanced intravital imaging combined with novel tools to dissect the cellular events involved in the generation and recall of T cell responses to localised virus infection, combined with a detailed functional analysis of the lymphoid organ stroma. Such fundamental information will contribute to the development of new generation vaccines and therapies to protect against tissue-specific infectious diseases, cancers and autoimmune diseases.Read moreRead less
Linkage Infrastructure, Equipment And Facilities - Grant ID: LE0989436
Funder
Australian Research Council
Funding Amount
$400,000.00
Summary
Multiphoton microscopy of living animals as a tool for immunology and cell biology studies. The multiphoton microscope will enable us to watch the growth, migration and interactions of cells in a living animal in response to changes in the cells' environment will give us better understanding of how we work as living machines, and what can go wrong with that process to make us unwell.
Defining the immunological roles of stromal cells within lymphoid tissues. The populations of endothelial and mesenchymal cells that construct the lymphoid tissues are being revealed as key players in the priming and orchestration of immune responses. Yet, fundamental knowledge of the molecular makeup and the functions of these stromal cells, particularly their roles in immune responses, is sorely lacking. This project will utilise a multidisciplinary approach including advanced imaging and bioi ....Defining the immunological roles of stromal cells within lymphoid tissues. The populations of endothelial and mesenchymal cells that construct the lymphoid tissues are being revealed as key players in the priming and orchestration of immune responses. Yet, fundamental knowledge of the molecular makeup and the functions of these stromal cells, particularly their roles in immune responses, is sorely lacking. This project will utilise a multidisciplinary approach including advanced imaging and bioinformatics to dissect the functions of the lymphoid stromal cells and their roles in the swelling of lymphoid tissues during immune responses. This will provide vital information about the biology of these understudied cells and reveal the ways in which they support the generation of immunity.Read moreRead less
Studies on the regulation of the pro-apoptotic protein Bim in mammalian development and cancer. This project is aimed at understanding the regulation of a gene, which is a tumour suppressor and is often mutated or down regulated in many different forms of cancers. A better understanding of how this gene works may eventually lead to better therapeutics to treat these cancers. This is relevant in the Australian context given that our aging population and obesity epidemics (the link between obesity ....Studies on the regulation of the pro-apoptotic protein Bim in mammalian development and cancer. This project is aimed at understanding the regulation of a gene, which is a tumour suppressor and is often mutated or down regulated in many different forms of cancers. A better understanding of how this gene works may eventually lead to better therapeutics to treat these cancers. This is relevant in the Australian context given that our aging population and obesity epidemics (the link between obesity, insulin resistance and various forms of cancers is well established) are leading to a rapid increase in new cancer cases, thus driving a rapid increase in demand for better treatments. This is particularly relevant in Indigenous health where obesity is on the rise following the transition from a traditional to an urban lifestyle.Read moreRead less
Mechanisms connecting diet, metabolism, gut microbiota and immunity. This project will identify the role of short chain fatty acids and the G-protein coupled receptor (GPR43) in regulating immune responses. This could explain how diet affects immune responses and also how certain bacteria in the gut provide benefits for immune defence.
The Function Of Histidine-rich Glycoprotein In Inflammation And Cancer
Funder
National Health and Medical Research Council
Funding Amount
$455,670.00
Summary
This research proposal investiagtes the role of a molecule known as histidine-rich glycoprotein (HRG) in the important diseases of cancer and inflammation. Inflammatory diseases can occur when the the normal checks on the immune system breakdown resulting in attacks on the body leading to tissue damage (e.g rheumatoid arthritis) and are significant contributors to morbidity and health costs in Australia. Cancer is the leading cause of death in Australia (28.4% of deaths in 2003). HRG has been im ....This research proposal investiagtes the role of a molecule known as histidine-rich glycoprotein (HRG) in the important diseases of cancer and inflammation. Inflammatory diseases can occur when the the normal checks on the immune system breakdown resulting in attacks on the body leading to tissue damage (e.g rheumatoid arthritis) and are significant contributors to morbidity and health costs in Australia. Cancer is the leading cause of death in Australia (28.4% of deaths in 2003). HRG has been implicated in controlling important aspects of inflammatory and cancer disease progression. Namely, HRG appears to regulate the formation and clearance of substances known as immune complexes - the primary cause of tissue damage in this disease. Furthermore, HRG may also control the process of cell invasion which is crucial for the migration of white blood cells of the immune system (leukocytes) to sites of inflammation to combat infections, and is also an important mechanism by which malignant tumour cells escape from primary tumour sites and spread throughout the circulation to other sites in the body. It is this process that makes cancer such a deadly disease. This study aims to define how HRG contributes to these important processes. This information may allow the development of new therapeutic approaches for the treatment of inflammatory diseases and cancer.Read moreRead less