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
Professor Godfrey is an immunologist with a long standing history as a pioneer in the study of a specialised type of white blood cell, known as NKT cells. NKT cells are activated in response to lipid-based molecules that are thought to alert the immune system, via NKT cell activation, to the presence of infectious agents or other abnormalities. A better understanding of how NKT cells function will provide new approaches to battling a broad range of diseases where these cells are implicated, incl ....Professor Godfrey is an immunologist with a long standing history as a pioneer in the study of a specialised type of white blood cell, known as NKT cells. NKT cells are activated in response to lipid-based molecules that are thought to alert the immune system, via NKT cell activation, to the presence of infectious agents or other abnormalities. A better understanding of how NKT cells function will provide new approaches to battling a broad range of diseases where these cells are implicated, including cancer, autoimmunity, allergy and infection.Read moreRead less
Understanding And Modulating The Human Immune System
Funder
National Health and Medical Research Council
Funding Amount
$470,144.00
Summary
T cells are the sentinels of our immune system continually scanning our tissue for abnormalities and eliminating threats in many forms. They are our second and last line of defence against microorganisms and cancer. Unfortunately, T cells can also cause harm through accidental crossreactvity or overzealous function. My work is directed at understanding how T cells work and how they can be controlled using drugs and gene therapy. If we can ‘tune’ the power of this master immune lineage we can unl
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.
Understanding The Mechanisms Of Action Of The ISCOMATRIX Adjuvant For The Development Of Human Vaccines
Funder
National Health and Medical Research Council
Funding Amount
$401,361.00
Summary
CSL Limited, an Australian owned global biopharmaceutical company, is developing the ISCOMATRIX (IMX) adjuvant for vaccines to prevent and treat serious human disease of global concern (e.g. cancer, pandemic flu, HPV, HCV). This study will identify the mechanisms of action of IMX in generating strong cellular immunity, how to enhance it further by combining with other immuno-modulators so as to develop novel IMX vaccines for the treatment of established cancer and persistent viral infections.
Investigating CD4+ T Helper Cell Differentiation During Blood-stage Plasmodium Infection
Funder
National Health and Medical Research Council
Funding Amount
$408,388.00
Summary
Some infections tend to afflict us only once, e.g. chickenpox, because our bodies develop immunity to these microbes relatively easily. In contrast, it takes many infections to develop immunity to the malaria parasite, because our immune systems seem to respond inefficiently to it. My work will improve our understanding of how the immune system is poorly activated during malaria, and may provide new ideas for boosting the immune system in response to malaria or indeed other infections.
The Role Of T Cell Receptor Avidity In Determining T Cell Repertoires And Responses
Funder
National Health and Medical Research Council
Funding Amount
$472,500.00
Summary
T cells are an essential component of the immune system. CD8 T cells, in particular, play a vital role in the immune response to viruses and tumors, predominantly via killing of virally infected cells and tumor cells, as well as the release of inflammatory mediators. T cells must be activated before they can mediate such anti-viral or anti-tumor effects and this activation occurs through the binding of pathogen or tumor fragments (peptides) by a receptor on the surface of T cells (T cell recepto ....T cells are an essential component of the immune system. CD8 T cells, in particular, play a vital role in the immune response to viruses and tumors, predominantly via killing of virally infected cells and tumor cells, as well as the release of inflammatory mediators. T cells must be activated before they can mediate such anti-viral or anti-tumor effects and this activation occurs through the binding of pathogen or tumor fragments (peptides) by a receptor on the surface of T cells (T cell receptor). Each individual has an entire repertoire of T cells with unique T cell receptors which interact with peptides with varying binding strengths. After stimulation of T cells by e.g. viral infection, a subset of the T cell repertoire will become expanded and dominate the anti-viral immune response. This study aims to investigate how, during a viral infection, the strength (or 'avidity') of the interaction between the T cell receptor and the peptide influences (i) whether or not a T cell clone is recruited into the immune response and, if so, its dominance over other clones within that response, and (ii) how efficiently a T cell is activated. It is anticipated that particular virus peptide-specific T cell populations with an overall high avidity will be better able to produce inflammatory mediators and kill infected cells compared to lower avidity T cell populations specific for a different virus peptide. It is also expected that the higher avidity populations will exhibit greater diversity of TCRs. Further, within peptide-specific populations, it is anticipated that the relatively high avidity T cell clones will dominate the specific response. This study will contribute to a greater understanding of factors contributing to T cell recruitment and activation. Armed with this knowledge we will be better able to design vaccines to elicit optimal T cell responses to viral infection.Read moreRead less
The Phenotype Of Protective Cytotoxic T Cell Responses During Viral Infections
Funder
National Health and Medical Research Council
Funding Amount
$841,114.00
Summary
T cell responses are important to establish protection against pathogens and some cancer via generation of memory cells that can be maintained long term and defeat promptly re-infections. This proposal aim at determining important factors that drive the success of immunological memory by employing single cell technologies and unique longitudinal samples from subjects infected with hepatitis C virus. The finding of this study will inform current vaccine research and immunotherapies.
CD4 T-cell Deficiency And Dysfunction In HIV Patients Receiving Effective Antiretroviral Therapy
Funder
National Health and Medical Research Council
Funding Amount
$490,020.00
Summary
Large numbers of people throughout the world will commence antiretroviral treatment for HIV infection over the next 5 years. This treatment partially corrects CD4 T-cell deficiency (the most characteristic immune defect caused by HIV infection) but does not restore the immune system to normal in patients who were very immunodeficient before treatment. This study will determine the cause of residual immune defects in patients receiving antiretroviral drugs with the aim of introducing new therapie ....Large numbers of people throughout the world will commence antiretroviral treatment for HIV infection over the next 5 years. This treatment partially corrects CD4 T-cell deficiency (the most characteristic immune defect caused by HIV infection) but does not restore the immune system to normal in patients who were very immunodeficient before treatment. This study will determine the cause of residual immune defects in patients receiving antiretroviral drugs with the aim of introducing new therapies to correct those defects. Our previous studies have demonstrated that the production of new T-cells in HIV patients receiving antiretroviral durgs is affected by the function of the thymus, but that this does not account for the production of all new T-cells. We will investigate other sites of T-cell production in the body. We have also previously shown that poor recovery of CD4 T-cells in patients successfully treated with antiretroviral drugs is associated with immune activation and that the T-cells do not function adequately, even when CD4 T-cell counts are substantially increased. We will determine whether these abnormalities are the result of a persistent defect in T cell activation by monocytes and-or dendritic cells. The findings of our studies will improve the treatment and life-expectancy of individuals with HIV infection.Read moreRead less