Elucidating Immune Responses By Single Cell Pedigree And Tracing Analysis
Funder
National Health and Medical Research Council
Funding Amount
$666,950.00
Summary
To develop vaccines and to combat autoimmunity, we need to understand how initial immune activation influences the fate of immune cells and their progeny. To achieve this, we have developed microscopic techniques and analytical software with which to observe how initial signalling processes in the parent immune cell influence the death, proliferation and differentiation of its daughters, granddaughters and further progeny. We will use these approaches to determine how immune cell fate is control
Discovery Of Novel T Cell Oncogenes By Using A Functional Retroviral CDNA Library Screen.
Funder
National Health and Medical Research Council
Funding Amount
$692,470.00
Summary
T cells mature in an organ called the thymus which is located on top of the heart. Blood borne T cell precursors enter the thymus after being resident in the bone marrow. T cell leukaemia is a disease where a blood cell that is committed to becoming a T cell is blocked from maturing into a functional cell. Instead, the leukaemic immature T cell uncontrollably divides to make endless non-functional copies of itself. As a result, normal functional T cells are outcompteted and the immune system is ....T cells mature in an organ called the thymus which is located on top of the heart. Blood borne T cell precursors enter the thymus after being resident in the bone marrow. T cell leukaemia is a disease where a blood cell that is committed to becoming a T cell is blocked from maturing into a functional cell. Instead, the leukaemic immature T cell uncontrollably divides to make endless non-functional copies of itself. As a result, normal functional T cells are outcompteted and the immune system is crippled. Patients generally die due to opportunistic infection. The molecular causes of T cell leukaemia are slowly being discovered. Up to 50% of all human T cell leukaemias overexpress SCL-TAL-1. Other T cell leukaemia-causing genes (oncogenes) include Ras and Notch. Current leukaemia treatments include chemotherapy and bone marrow transplants but even these fail ~30% of the time. Consequently, all T cell oncogenes need to be discovered so that disease-specific treatments can be generated. This proposal will utlise a functional retroviral cDNA library screen to uncover novel T cell lineage commitment genes and T cell oncogenes. This will be accomplished by constructing a coloured [GFP] cDNA library (a library of genes) that will be transfected (inserted) into immature T cells that cannot develop down the T cell pathway owing to the lack of a crucial gene (Rag-1). The T cell oncogene Ras and the T cell lineage commitment gene Notch can move cells past the Rag-1 block. If there is a gene in the cDNA library that can compensate for the lack of Rag-1 and allow the cells to mature we will detect it using high speed flow cytometryic cell sorting (like sieving weevils from flour very quickly). Once we find this cell we will isolate the gene using the colour tag. The potential oncogenes uncovered will provide the foundation for next generation drug development that targets each leukaemia based on its cause.Read moreRead less
My research centers on the formation and function of T cells, with particular emphasis on normal T cell homeostasis and how T cells respond to foreign antigens while tolerating self antigens.
Regulation Of T Cell Effector Function In Peripheral Tissues
Funder
National Health and Medical Research Council
Funding Amount
$698,550.00
Summary
Protection from infections relies on different types of immune cells. While some of these cells are found in the blood, others reside in peripheral tissues such as the skin. We will analyse the function of these peripheral immune cells to understand how they work to fight off infections. We will also investigate how so-called memory cells that permanently reside in peripheral tissues can protect from re-infection with similar bacteria or viruses.
The Role Of Epigenetic And Transcriptional Regulation In CD8+ T Cell Effector Gene Expression.
Funder
National Health and Medical Research Council
Funding Amount
$72,571.00
Summary
All cells contain DNA that is tightly wrapped around proteins, whereby changes in the structure allow for the expression of proteins. Cells of the immune system express proteins that can resolve viral infections. This study plans to examine the factors mediating the changes in DNA that allow for the expression of these proteins in immune cells. Insights will enable a greater understanding of how these proteins are generated and maintained, and hence will have implications for vaccine design.
The Molecular Identification Of FoxP3 +ve Regulatory T Cells
Funder
National Health and Medical Research Council
Funding Amount
$483,273.00
Summary
The immune system has a series of checks and balances in place to distinguish foreign bodies from normal, or self-antigens. In healthy individuals this prevents the immune system from attacking the cells and tissues of the body, food proteins, and the beneficial bacteria of the gut. However in autoimmune disease the system becomes imbalanced, allowing reactions to benign antigens, causing diseases such as diabetes, asthma and rheumatoid arthritis. One of the key players in the maintenance of a h ....The immune system has a series of checks and balances in place to distinguish foreign bodies from normal, or self-antigens. In healthy individuals this prevents the immune system from attacking the cells and tissues of the body, food proteins, and the beneficial bacteria of the gut. However in autoimmune disease the system becomes imbalanced, allowing reactions to benign antigens, causing diseases such as diabetes, asthma and rheumatoid arthritis. One of the key players in the maintenance of a healthy immune system is a specialized set of T cells known as T Regulatory cells. These cells are rare, at 1-4% of all T cells, yet are potent modulators of other T cells, and can prevent the activation of a T cell if it is reacting to a self-antigen. If they can control the cause of autoimmune disease, and patient Treg cells can be manipulated, it may be possible to use them therapeutically. Recently the switch that is required to generate regulatory cells was identified from patients with a rare autoimmune disease called Immunodysregulation, polyendocrynopathy, enteropathy, X-linked syndrome or IPEX. A mouse disease, Scurfy, with similar symptoms, is caused by the same mutations. The mutated gene encodes a protein, FoxP3, and this protein is able to bind to other genes in T cells and regulate their function. Without this protein, there are no T regulatory cells, resulting in autoimmune disorders. At this time there is very little known about how the FoxP3 gene is able to make a T cell become a regulatory T cell, and nothing is known about the genes that are turned off and on to facilitate this. If we can understand better the role of this protein, FoxP3, in the generation and maintenance of T cells with regulatory function, we may better be able to diagnose and treat autoimmune diseases, and this knowledge will have broad application to many autoimmune disorders.Read moreRead less
Identifying The Ontogeny And Fate Of T Follicular Helper Cells By Two-photon Photoconversion
Funder
National Health and Medical Research Council
Funding Amount
$623,070.00
Summary
The aim of this proposal is to investigate immune cells called T follicular helper cells using a novel microscopy-based method that we have developed. This method lets us ‘tag’ these cells in a way that enables us to distinguish them from all other cells and follow them as they migrate to different immunological compartments during the response. T follicular helper cells are important for protective immune responses against pathogens and a better understanding of this T cell subset will aid vacc ....The aim of this proposal is to investigate immune cells called T follicular helper cells using a novel microscopy-based method that we have developed. This method lets us ‘tag’ these cells in a way that enables us to distinguish them from all other cells and follow them as they migrate to different immunological compartments during the response. T follicular helper cells are important for protective immune responses against pathogens and a better understanding of this T cell subset will aid vaccine design.Read moreRead less