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.
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.
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
Structure And Composition Of The Pre-T Cell Receptor-CD3 Complex
Funder
National Health and Medical Research Council
Funding Amount
$307,946.00
Summary
In order to recognize a wide variety of pathogens, humans produce many different T cell receptors (TCRs) by the process of gene-rearrangement. However, gene-rearrangement may not always lead to a functioning TCR. We are studying the pre-TCR protein that is responsible for monitoring the success of gene-rearrangement and is thus essential for the formation of a robust immune system. Understanding pre-TCR function will lead to new treatments for immune related diseases.
Members Of The CMRF-35 Leukocyte Receptor Complex On Human Chromosome 17q22-24 Modulate Immune Function
Funder
National Health and Medical Research Council
Funding Amount
$489,750.00
Summary
We have identified and characterized a group of proteins on the surface of different white blood cells called the CMRF-35 molecules. We hypothesize that these molecules play a role in regulating an immune response by acting as thermostat molecules i.e. molecules able to trigger or inhibit the immune response. This project aims to define the role of two of these molecules in regulating white blood cells in their response to foreign molecules or antigens. This project will have significant impact ....We have identified and characterized a group of proteins on the surface of different white blood cells called the CMRF-35 molecules. We hypothesize that these molecules play a role in regulating an immune response by acting as thermostat molecules i.e. molecules able to trigger or inhibit the immune response. This project aims to define the role of two of these molecules in regulating white blood cells in their response to foreign molecules or antigens. This project will have significant impact on understanding whether these triggering and inhibitory signals initiated from the CMRF-35 molecules effects i) how the cells divide, ii) what molecules are secreted by the cells, iii) whether the cells can mature or iv) whether a cell survives or dies. Some of the molecules involved in sending these signals will be identified. The ability to trigger or inhibit cellular effects through these molecules may be important in some forms of myeloid leukemia and in the ability to help manipulate the immune response to fight tumors.Read moreRead less
Kinetics, Mechanism And Engraftment Of In Vitro Generated T Cell Precursors As A Strategy To Enhance Thymic Rejuvenation Following Allogeneic Hematopoietic Stem Cell Transplantation
Funder
National Health and Medical Research Council
Funding Amount
$403,324.00
Summary
Immune regeneration - following standard cancer therapies such as chemotherapy and radiation-therapy for hematopoietic (blood) stem cell transplant (HSCT) - is one of the most significant unmet clinical challenges today. This research will focus on using “off the shelf” precursor T cells to improve immune reconstitution following HSCT, thereby significantly reducing the incidence of morbidity and mortality following transplantation.
Asymmetric Cell Divison In T Cell Development: Consequences For Immunity And Cancer
Funder
National Health and Medical Research Council
Funding Amount
$642,608.00
Summary
Human health depends upon the development of an immune system that can effectively control infection without damaging normal tissue. In this project, we assess a new paradigm by which immune cell development might be controlled, in which an immune cell precursor divides in such a way that its two daughters inherit different molecular constitutents that subsequently regulate the adoption of different cell fate. The likely consequences of this phenomonon on immunity and cancer will be explored.
The lymphocyte plays a vital role in our immune defence. When lymphocytes encounter a foreign invader, such as a virus, they make a series of decisions that influence the strength, type, and longevity of the immunity created. This program aims to understand how lymphocytes make decisions at the molecular level that affect cell and whole of system level behaviour. We aim to improve vaccines and understand diseases such as allergy, lupus, arthritis and leukaemia to develop novel therapies.