The Genetics Governing The Specificity Of T Cell Receptors For Peptide-MHC
Funder
National Health and Medical Research Council
Funding Amount
$303,828.00
Summary
T lymphocytes play a pivotal role in the immune system by recognising virus-infected tissue through the use of highly specific cell surface receptors. These T cell receptors (TCR) recognise viral peptides (p) presented by MHC molecules on the surface of virus-infected cells. For a TCR to be successfully triggered, it must lock onto an exact 3-dimentional pMHC match. In this way, any given TCR must simultaneously recognise both the viral peptide and the MHC presenting it. Such recognition must be ....T lymphocytes play a pivotal role in the immune system by recognising virus-infected tissue through the use of highly specific cell surface receptors. These T cell receptors (TCR) recognise viral peptides (p) presented by MHC molecules on the surface of virus-infected cells. For a TCR to be successfully triggered, it must lock onto an exact 3-dimentional pMHC match. In this way, any given TCR must simultaneously recognise both the viral peptide and the MHC presenting it. Such recognition must be sensitive and precise since a false positive could result in destruction of healthy tissue. There are a huge variety of TCRs and pMHCs, but there are only a few examples where the precise molecular interactions within the TCR-pMHC complex are known. Surprisingly, these studies have shown very limited consistency in the way the TCRs bind the pMHCs and therefore, the structural rules that underlie why TCRs consistently bind MHC remains a mystery of critical importance to this fundamental feature of the immune system. In this proposal, we will attempt to elucidate the rules of TCR-pMHC engagement. Another question to be addressed in this proposal is: During a viral infection, why are certain TCRs chosen above others that also have the capacity to recognise the same viral peptide? By investigating exactly which feature-s of these receptors predisposes their supremacy, we may be better able to predict the outcome of a pathogen attack and to even one day build our own super receptors. Finally, this proposal will also investigate how natural mutations in TCR genes across the human population affect our individual responses to viruses. Overall, advances in each of these core areas of medical research will aid in the development of new intelligent vaccines and individualised drugs for the treatment of cancer and infectious disease.Read moreRead less
Investigations Into The Biology And Functionality Of The Human T Cell Receptor
Funder
National Health and Medical Research Council
Funding Amount
$424,262.00
Summary
T lymphocytes play a pivotal role in the immune system by recognising virus-infected tissue and tumour cells through the use of specific cell surface receptors called T cell receptors (TCR). This project will study why partcular TCRs are used by the immune system, and will also examine the specificity of T cell recognition by determine the range of molecules an individual T cell can recognise. The work will aid in the development of new intelligent vaccines for cancer and infectious disease.
I am a Clinical Immunologist, Immunopathologist, clinical researcher and laboratory scientist exploring the interactions between T cell and viral infections. My area of particular interest is the mechanisms by which HIV infection subverts effective T cel
Interactions Between Adaptable Pathogens, Drugs And The Human Host
Funder
National Health and Medical Research Council
Funding Amount
$5,727,327.00
Summary
The Centre for Clinical Immunology and Biomedical Statistics (CCIBS) represents a collaboration between Royal Perth Hospital and Murdoch University that has brought together internationally recognised expertise in clinical immunology, experimental biology and innovation in biostatistics and computing. These resources have been applied to a broad range of research issues within the broad framework of HIV and hepatitis C disease and treatment. CCIBS has become a leading centre of research excellen ....The Centre for Clinical Immunology and Biomedical Statistics (CCIBS) represents a collaboration between Royal Perth Hospital and Murdoch University that has brought together internationally recognised expertise in clinical immunology, experimental biology and innovation in biostatistics and computing. These resources have been applied to a broad range of research issues within the broad framework of HIV and hepatitis C disease and treatment. CCIBS has become a leading centre of research excellence internationally, establishing a reputation for innovative approaches to host-viral interactions that are built on a long tradition of research into the population genetics of both human and viral genomes, combined with a willingness to negotiate complex computation and statistical challenges in order to faithfully reflect dynamic biological processes at a population level. An early recognition that large and integrated repositories of genetic and clinical data are fundamental to the research success in the genomic era has also led to the creation of the single most comprehensive repository of HIV genetic sequencing data in the world. The contributions that CCIBS has made to several distinct areas of research, including understanding viral adaptation to host immune responses, the development of genetic testing to predict drug hypersensitivity reactions, and causes of antiretroviral drug-associated toxicities, have been published in prestigious journals including Science, Nature, Nature Immunology, The Lancet, Proceedings of National Academy of Sciences, and The American Journal of Human Genetics, and have also resulted in numerous international collaborations that recognise the unique attributes that CCIBS has been able to bring to the global research effort aimed at understanding fundamental aspects of HIV and hepatitis C biology and treatment.Read moreRead less
Identification And Characterisation Of HLA-E Restricted Influenza A Virus-specific CD8+ T Cells
Funder
National Health and Medical Research Council
Funding Amount
$354,156.00
Summary
With seasonal epidemics and the continual threat of a pandemic, there is an urgent need for a one-shot universal vaccine that protects against different influenza strains. This can potentially be achieved by the activation of killer T cells. I will identify new virus targets presented by a highly conserved human protein. Killer T cell recognition of these targets may provide a unique opportunity to develop an improved vaccine.
The introduction of novel viruses such as influenza and Henipa viruses into the human population from animal reservoirs is often fatal as the virus is not attenuated by adaptation to the host. As we are immunologically naïve, efficient immunity cannot be mounted. T cells mediate the control and clearance of viruses, and can remember past infection or vaccination. Understanding the role of T responses to zoonotic viral infections is needed for development of novel preventative vaccines.
Real Time Visualisation Of T Cell Cycling During Influenza Immune Responses
Funder
National Health and Medical Research Council
Funding Amount
$589,679.00
Summary
Influenza remains a major health threat, particularly in the elderly population. Here we will unravel the mechanisms underlying the expansion of killer T cells, a crucial part of the anti-influenza immune response. Using intravital multi-photon microscopy, we will follow the cell cycle dynamics of individual T cells in real time during different stages of influenza. We will further elucidate how ageing impacts on T cell proliferation. Together, this will provide insight into the mechanisms of an ....Influenza remains a major health threat, particularly in the elderly population. Here we will unravel the mechanisms underlying the expansion of killer T cells, a crucial part of the anti-influenza immune response. Using intravital multi-photon microscopy, we will follow the cell cycle dynamics of individual T cells in real time during different stages of influenza. We will further elucidate how ageing impacts on T cell proliferation. Together, this will provide insight into the mechanisms of anti-viral immunity and immuno-senescence.Read moreRead less
Mechanisms That Control Epstein Barr Virus Infection And Their Dysregulation In X-linked Lymphoproliferative Disease
Funder
National Health and Medical Research Council
Funding Amount
$453,986.00
Summary
EBV is ubiquitous virus that infects more than 90% of the population worldwide. Although infection is largely asymptomatic in most healthy individuals, EBV is nonetheless associated with the development of at least 7 distinct types of human malignancies. Most importantly, EBV is still a huge healthy problem in conditions of immune suppression. Therefore a better understanding of the mechanisms involved in effective control of the virus will help develop better immune therapies and vaccines.