Determining The Role Of DOCK8 In CD4+ T And B Cell Differentiation And Its Implications On Autosomal Recessive Hyper IgE Syndrome (AR-HIES)
Funder
National Health and Medical Research Council
Funding Amount
$512,600.00
Summary
Autosomal recessive hyper IgE (AR-HIES) syndrome due to mutations in DOCK8 is a rare primary immunodeficiency whereby patients present with susceptibility to severe and recurrent viral infections as well as an increased risk of developing cancer, severe food and environmental allergies, and atopic disease characterised by hyper IgE and extreme eosinophilia. This grant will investigate how abnormal DOCK8 function in CD4+ T cells and B cells contributes to disease pathogenesis in AR-HIES patients.
This application proposes to study in detail the main target cell for HIV infection, namely CCR5+ CD4 T lymphocytes. After 30 years of the pandemic, fundamental knowledge of these cells, such as locations in the body, differentiation from other lymphocytes, and survival, is still lacking. These attributes determine whether or not they will be infected by HIV, whether this can be prevented by vaccines or CCR5 blocking drugs, and whether their long-term survival results in an inability to eradicat ....This application proposes to study in detail the main target cell for HIV infection, namely CCR5+ CD4 T lymphocytes. After 30 years of the pandemic, fundamental knowledge of these cells, such as locations in the body, differentiation from other lymphocytes, and survival, is still lacking. These attributes determine whether or not they will be infected by HIV, whether this can be prevented by vaccines or CCR5 blocking drugs, and whether their long-term survival results in an inability to eradicate HIV.Read moreRead less
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.
Regulation Of T Follicular Helper Cell Development And Effector Function In Health And Disease
Funder
National Health and Medical Research Council
Funding Amount
$419,197.00
Summary
Immune cells mature into distinct populations with specialized functions. One subsets are T follicular helper (TFH) cells which are important for instructing B cells to produce antibodies following infection or vaccination. The means by which TFH cells are generated are unknown. We will determine mechanisms whereby TFH cells are produced and how they function. We hope to design approaches that will modulate the function of TFH cells in cases of immunodeficiencies, autoimmunity or vaccination.
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
Population Dynamics Of Tissue-specific Effector And Regulatory CD4+ T Cells
Funder
National Health and Medical Research Council
Funding Amount
$394,250.00
Summary
Survival of white blood cells in the body is an active process and is important for the maintainence of a T cell population which can recognise a wide variety of foreign antigens. At present the fate of T lymphocytes which recognise self antigens is unclear. Knowledge of the survival kinetics of self-reactive T lymphocytes and the mechanism by which they are regulated in the normal individual is crucial to be able to control the development of various diseases, including autoimmune diseases. Fro ....Survival of white blood cells in the body is an active process and is important for the maintainence of a T cell population which can recognise a wide variety of foreign antigens. At present the fate of T lymphocytes which recognise self antigens is unclear. Knowledge of the survival kinetics of self-reactive T lymphocytes and the mechanism by which they are regulated in the normal individual is crucial to be able to control the development of various diseases, including autoimmune diseases. From our previous studies of autoimmune gastritis we have generated cell lines of lymphocytes that recognise stomach-specific antigens and with these unique reagents we will perform experiments to determine the fate of these self-reactive T cells in a normal individual. Also we will determine the impact of different amounts of the tissue antigens on the survival and activation of self-reactive T cells, and finally how a special class of lymphocytes, know as regulatory lymphocytes, act in vivo to control the activity of self-reactive T cells. We will use not only classical immunological approaches to address these issues but also state of the art imaging, to visualise the nature of the cell interactions in living tissues. The information arising from this work will underpin strategies to selectively turn off self-reactive lymphocytes that cause disease, will form the basis of clinical development of cell based therapies to treat autoimmune diseases, and the imaging technologies developed in this grant will have wide applicability to the study of a range of immune responses.Read moreRead less