Role Of Dendritic Cell Subsets In The Generation Of CD4 T Cell Memory
Funder
National Health and Medical Research Council
Funding Amount
$563,554.00
Summary
This project studies the mechanisms responsible for establishing immunologic memory that is generated by vaccination and determines its efficacy. We aim to identify and study previously unacknowledged factors that critically affect the efficacy of vaccination. The results will be significant for both preventative and therapeutic vaccination (cancer, autoimmunity) and will help us to design new vaccines to improve immune function in infection, autoimmunity and cancer.
CD4+ T Cell-independent Immunity Against Salmonellae
Funder
National Health and Medical Research Council
Funding Amount
$550,226.00
Summary
Salmonella typhimurium is an important pathogen in both developed and developing countries where it causes significant HIV-linked morbidity. There is a pressing need to understand how immunity might be established against this organism that will function when the patient is immunocompromised either through age or through a comorbidity like HIV.
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
Understanding The Role Of CD4 T Cells In Viral Infection: A Means Of Improving Anti-viral Immunotherapy.
Funder
National Health and Medical Research Council
Funding Amount
$672,009.00
Summary
Development of therapies to prevent and treat chronic infections is of the highest priority as they cause considerable clinical challenges and on-going health care costs. Efforts to improve treatment of chronic viral infections, such as those caused by HIV, hepatitis C virus and human cytomegalovirus, require a better understanding of the immune responses needed to control these viruses long-term. This proposal will investigate the role of CD4+ T cells in controlling chronic viral infection.
Using Single-cell Genomics To Resolve Functional Diversification By CD4+ T Cells In Vivo
Funder
National Health and Medical Research Council
Funding Amount
$1,048,096.00
Summary
During immune responses, individual CD4+ T cells multiply and produce hundreds of descendants, with close relatives within a family often developing very different skills. How such differences emerge from one ancestor remains unclear. We use new methods to look at individual CD4+ T cells in unprecedented detail, allowing us to see how close relatives begin to grow apart. Using this, we hope to find novel ways of educating CD4+ T cells to prevent infectious and immune-mediated diseases.
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
Follicular T Helper Cells: Critical Regulators Of Humoral Immune Responses
Funder
National Health and Medical Research Council
Funding Amount
$272,591.00
Summary
B cells are important cells of the immune system that are responsible for producing antibodies in response to infection with pathogens, such as bacteria or viruses, or following vaccinations. In order for B cells to accomplish this task, they require help from a specialised popualtion of T cells, which are another type of immune cell - these are known as follicular T helper (TFH) cells. Under normal circumstances, T cells and B cells specifically interact with one another within lymphoid tissues ....B cells are important cells of the immune system that are responsible for producing antibodies in response to infection with pathogens, such as bacteria or viruses, or following vaccinations. In order for B cells to accomplish this task, they require help from a specialised popualtion of T cells, which are another type of immune cell - these are known as follicular T helper (TFH) cells. Under normal circumstances, T cells and B cells specifically interact with one another within lymphoid tissues such as tonsils, spleens and lymph nodes - here, they engage in a dialogue, the end result of which is the B cells being instructed to produce the appropriate type of antibodies by T cells. However, if tis process is not regulated, the T cells can deliver too little of too much help - this can result in several different types of diseases of the immune system, such as immunodeficiencies (ie insufficient production of antibodies, resulting in individuals becoming susceptible to infections) or autoimmunity (ie production of inappropriate types of antibodies that can recognise cells of the host, resulting in tissue damage and organ failure). The means by which TFH cells instruct B cells to produce antibodies is not completely understood. This project will seek to determine the mechanism whereby TFH cells carry out this important function by performing detailed examination of them follwoing their removal from tissues such as human tonsils and spleens. In doing so, we hope to design approaches that will allow the function of TFH cells to be improved in cases of immunodeficiencies, or suppressed in situations of autoimmune diseases.Read moreRead less