The Transcription Factors C-Rel And RelA Serve Distinct Roles In The Devlopment And Function Of CD4 Regulatory T Cells
Funder
National Health and Medical Research Council
Funding Amount
$492,991.00
Summary
An unfortunate consequence of immune function is that occasionally rogue immune cells are produced that attack the host and lead to the development of so-called autoimmune diseases such as arthritis. Normally a white blood cell called a regulatory T cell suppresses these self reactive immune cells. We have identified factors that govern genetic programs in regulatory T cells. Understanding how these factors work should permit the development of new strategies to combat autoimmune diseases.
Interleukin Signalling In CD4+ T Cell Differentiation
Funder
National Health and Medical Research Council
Funding Amount
$663,919.00
Summary
Our bodies rely on the production of antibodies to fight infection. The cytokine IL-21 is produced by immune cells called T follicular helper (Tfh) cells that help B cells make antibodies. Tfh cells, in turn, are controlled by regulatory (Tfr) cells. Our findings demonstrate that IL-21 supports Tfh cells and limits Tfr cells, thus favoring antibody production and long term immunity. Using genomic and cellular approaches, the mechanism(s) underlying these observations will be explored.
The Function Of Transcription Factor SCL In T Cell Development.
Funder
National Health and Medical Research Council
Funding Amount
$504,750.00
Summary
SCL is a gene which is abnormally expressed in a large percentage of human T cell leukaemias. Mouse models that increase SCL levels have demonstrated that T cell maturation is abnormally affected by SCL. Thus, providing a clue as to how T cell leukemias arise. By utilising recombinant DNA technology we are now able to control SCL levels in T cell maturation. We can either increase the level of SCL using pharmacological reagents or we can genetically remove SCL from maturing T cells. This double- ....SCL is a gene which is abnormally expressed in a large percentage of human T cell leukaemias. Mouse models that increase SCL levels have demonstrated that T cell maturation is abnormally affected by SCL. Thus, providing a clue as to how T cell leukemias arise. By utilising recombinant DNA technology we are now able to control SCL levels in T cell maturation. We can either increase the level of SCL using pharmacological reagents or we can genetically remove SCL from maturing T cells. This double-edged approach will allow us to monitor the effects of SCL on maturing T cells with a precision that has never previously been achieved. Results from this approach will provide new insights into how T cell leukaemia develops and provide the foundation for new rational based treatments.Read moreRead less
The Structure And Composition Of The T-cell Receptor-CD3 Complex
Funder
National Health and Medical Research Council
Funding Amount
$434,644.00
Summary
Our research will provide a fundamental advance in our understanding of how foreign viruses and pathogens trigger the immune system. Gaining a greater understanding of these central events will facilitate the design of novel therapies to treat immune associated disorders such as transplant rejection, autoimmune disease and some cancers.
Characterisation And Development Of Type-2 NKT Cells
Funder
National Health and Medical Research Council
Funding Amount
$853,885.00
Summary
Humans defend themselves from foreign pathogens by mounting a protective immune response. Type-2 NKT cells recognise foreign lipid molecules and play a key role in immunity. This project is designed to understand to how Type-2 NKT cells develop within the body, how they recognise lipid molecules and how they carry out their immune functions. This work will have important implications in understanding the role of NKT cells in human health and disease.
Delineating Immune Circuits For Innate And Adaptive Immune Protection
Funder
National Health and Medical Research Council
Funding Amount
$876,005.00
Summary
The immune system provides the essential frame-work to protect us against infection, disease and to heal tissues after trauma. This is achieved by a complex but elegant network of different types of white blood cells. Understanding the molecular wiring of these cells will provides fundamental insights to how the body fights pathogen infections and cancer and lays the foundation to therapeutic approaches to vaccination and disease treatments.
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
The human immune system comprises many different types of cells that can detect foreign molecules. My research will lead the way to understanding some of the most abundant, yet least well understood, cells within this system, collectively known as 'unconventional T cells'. This knowledge is essential to optimally and efficiently manipulate the immune system in health and disease.
Following The T Cell Repertoire Over The Human Life Course
Funder
National Health and Medical Research Council
Funding Amount
$473,159.00
Summary
T cells are critical to human health being our second and last line against infectious disease and cancer. However, we know very little about how this important immune compartment operates on a top-down scale. This project will use new technology to resolve this immune compartment to high detail. We will then use this new method to track the T cell compartment from the first years of life and across years of adult life to see how this vital immune compartment evolves along the human life course.