Changes In The Fate Of Thymic Emigrants During Foetal And Postnatal Development In Sheep
Funder
National Health and Medical Research Council
Funding Amount
$62,744.00
Summary
SIGNIFICANCE The mature T cell pool can arise from only two sources, either thymic export or expansion of the peripheral T cell pool or a mixture of both. The lifespan of either cell type, i.e. recent thymic emigrants or mature T cell, has considerable implications for the development of the T cell repertoire. Recent thymic emigrants represent a wide diversity of positively selected thymocytes but mature T cell pool expansion results in reduced diversity because of a predominant expansion of a l ....SIGNIFICANCE The mature T cell pool can arise from only two sources, either thymic export or expansion of the peripheral T cell pool or a mixture of both. The lifespan of either cell type, i.e. recent thymic emigrants or mature T cell, has considerable implications for the development of the T cell repertoire. Recent thymic emigrants represent a wide diversity of positively selected thymocytes but mature T cell pool expansion results in reduced diversity because of a predominant expansion of a limited number of clones. A high rate of continuous substitution of mature T cells in the peripheral pool with freshly arriving recent thymic emigrants exhibiting newly arising TCR not previously existing will produce higher adaptive capabilities for the immune system. We have developed techniques for labeling the thymus in vivo by intra-thymic injection with the long-term lymphocyte tracking dye CFSE. We can establish a cohort of labeled recent thymic emigrants and we can, for the first time in any experimental system, track directly the survival, death or division of recent thymic emigrants and their progeny together with their tissue homing properties and surface markers for periods of many months after they leave the thymus. This will enable us to determine the way in which the pool of mature T cells is built up during the formation of the foetal immune system and the way the mature T cell population is established and maintained in postnatal life.Read moreRead less
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
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
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.