Epigenetic Regulation Of CD8+ T Cell Function And Memory.
Funder
National Health and Medical Research Council
Funding Amount
$578,171.00
Summary
Upon virus infection, a subset of white blood cells, called killer T cells, are recruited to fight the infection. This proposal aims to examine molecular changes that occur within killer T cells and impart their specific function. We also aim to understand how killer T cells are _programmed� as they establish immunological memory. This proposal will provide insights important for the design and improvement of vaccine strategies to fight pathogens such as influenza, HIV and even tumors.
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
Regulation Of TNF And SFK Signalling In Immune Cells By TCPTP
Funder
National Health and Medical Research Council
Funding Amount
$454,023.00
Summary
Tumour necrosis factor (TNF) is a potent proinflammatory cytokine that plays an important role in immunity and inflammation. TNF acts on the cell surface to activate two key cellular communication or signalling pathways: the mitogen-activated protein kinase (MAPK) pathway and the nuclear factor kappaB (NFkappaB) pathway. The relative activation of the two pathways can dictate whether cells live and proliferate or differentiate or otherwise die in response to TNF, and therefore determine the natu ....Tumour necrosis factor (TNF) is a potent proinflammatory cytokine that plays an important role in immunity and inflammation. TNF acts on the cell surface to activate two key cellular communication or signalling pathways: the mitogen-activated protein kinase (MAPK) pathway and the nuclear factor kappaB (NFkappaB) pathway. The relative activation of the two pathways can dictate whether cells live and proliferate or differentiate or otherwise die in response to TNF, and therefore determine the nature of the immune or inflammatory response. The T-cell protein tyrosine phosphatase (TCPTP) is known to be important in the immune system and serves as a negative regulator of inflammation. Our preliminary studies have identified TCPTP as a selective regulator of TNF-induced MAPK but not NFkappaB signaling. TCPTP exerts its effects by inactivating Src family kinases (SFK) which are themselves integral to immune and inflammatory responses. In this proposal we will elucidate the molecular basis for TCPTP function in TNF- signalling and characterise the role of TCPTP in TNF and SFK functions in immune cells, in particular T-cells.Read moreRead less
Transcriptional Regulation And The Role Of Key Histone Variants In Defining Gene-specific Chromatin States.
Funder
National Health and Medical Research Council
Funding Amount
$450,696.00
Summary
One of the most outstanding and significant questions within this genome era has been to unravel how chromatin structure within the nucleus of a cell is capable of regulating the complex expression patterns needed for cell proliferation, cell differentiation and cellular responses to environmental factors such as pathogens and signaling molecules. Studies on lower eukaryotes have demonstrated that deposition of histone variants provides a powerful mechanism for modulating chromatin structure. To ....One of the most outstanding and significant questions within this genome era has been to unravel how chromatin structure within the nucleus of a cell is capable of regulating the complex expression patterns needed for cell proliferation, cell differentiation and cellular responses to environmental factors such as pathogens and signaling molecules. Studies on lower eukaryotes have demonstrated that deposition of histone variants provides a powerful mechanism for modulating chromatin structure. To date, there is no comprehensive picture of the contribution of histone variants in the transcriptional process in higher eukaryotes. Preliminary results obtained in our laboratory have provided fascinating first insights into the role of key histone variants in the control of regulatory regions of key genes involved in the immune system. Importantly, these results have enabled us to identify a novel chromatin regulatory mechanism that this proposal aims to investigate in necessary detail. The outcome of the proposed research will give an in depth understanding on how chromatin structure is influenced by the recruitment of histone variants and how this mechanism is crucially involved in gene regulation. Crucially, we will attempt to answer some of the most outstanding and significant questions about how chromatin dynamics within the nucleus switch on-off a defined subset of genes in response to a particular environmental stimulus. In addition, the new level of understanding of the events in metastasis-invasion will help provide advances in cancer and gene therapy.Read moreRead less
Long-lived CD8 T Cell Responses Induced By A Recombinant Cytomegalovirus Vector
Funder
National Health and Medical Research Council
Funding Amount
$234,750.00
Summary
The priming of the immune system to protect against infection and disease is an important means to alleviate these conditions. Current vaccination technologies often rely on multiple inoculations (prime-boosting). In addition, specific priming of the immune system against pathogens that target mucosal sites has been difficult and often lacks efficacy resulting in temporary or variable protection. Using a well developed mouse model for a common human virus, we have explored the potential of this ....The priming of the immune system to protect against infection and disease is an important means to alleviate these conditions. Current vaccination technologies often rely on multiple inoculations (prime-boosting). In addition, specific priming of the immune system against pathogens that target mucosal sites has been difficult and often lacks efficacy resulting in temporary or variable protection. Using a well developed mouse model for a common human virus, we have explored the potential of this agent as a vaccine agent, making use of its long term persistence in the infected host to provide continued antigenic stimulation of the immune system. We have found that very strong and long lasting responses can be elicited after a single inoculation of avirulent virus. In this study, this effect will be further explored and developed.Read moreRead less
Costimulatory Mechanisms For Enhancing CD8 T Cell Responses During An Acute Respiratory Infection
Funder
National Health and Medical Research Council
Funding Amount
$438,750.00
Summary
Following an infection, a person's immune system responds to fight the pathogen. One of the most important consequences of the immune response to an infectious disease is the establishment of memory to that particular disease so that a person is able to clear the same pathogen faster upon subsequent exposures. This memory is due to specific cells called memory lymphocytes. One subset of these cells are called CD8+ T cells and these are important for controlling and clearing viral infections. New ....Following an infection, a person's immune system responds to fight the pathogen. One of the most important consequences of the immune response to an infectious disease is the establishment of memory to that particular disease so that a person is able to clear the same pathogen faster upon subsequent exposures. This memory is due to specific cells called memory lymphocytes. One subset of these cells are called CD8+ T cells and these are important for controlling and clearing viral infections. New vaccine strategies are aimed at improving CD8 T cell responses so that they are more effective at fighting diseases such as HIV which causes AIDS and Hepatitis C virus. The mechanisms which lead to long lived memory CD8 T cells are not well understood. This research will characterise the function of genes involved in activating CD8 T cells and producing more memory CD8 T cells. The influenza model will be used as it is a well characterised model for studying anti-viral immunity. This project involved studying the mechansims of known genes involved in CD8 T cell responses to influenza. Also the discovery of new genes which are involved in CD8 T cell memory will be identified and characterised using new novel technologies, such as ENU mutagenesis, that only now are able to be utilised since the mouse genome (DNA) has been sequenced. This research will provide a basis for design of new and more effective vaccines.Read moreRead less