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.
A Novel CCR2-dependent Niche For CD8+ T Cell Memory
Funder
National Health and Medical Research Council
Funding Amount
$482,549.00
Summary
In this project, we will determine how a protein called CCR2 controls the generation of memory immune responses and whether its activity can be manipulated to enhance vaccination.
Effector And Memory CD8+ T Cell Responses To Engineered Influenza A Escape Mutants
Funder
National Health and Medical Research Council
Funding Amount
$465,210.00
Summary
T cells are a critical component of the immune system after infection with viruses. In particular, virus-specific CD8+ T cells can clear viral infections by killing virally-infected cells and the release of immunomodulators. These are called effector T cells. After the viral infection is cleared, a small proportion of T cells (around 5 to 10%) survives for many years and constitute a memory pool of virus-specific T cells. Memory T cells provide a rapid and effective protection in case of a repea ....T cells are a critical component of the immune system after infection with viruses. In particular, virus-specific CD8+ T cells can clear viral infections by killing virally-infected cells and the release of immunomodulators. These are called effector T cells. After the viral infection is cleared, a small proportion of T cells (around 5 to 10%) survives for many years and constitute a memory pool of virus-specific T cells. Memory T cells provide a rapid and effective protection in case of a repeated infection with the same virus, and hence result in a less severe disease. However, viruses often mutate their genes to escape such efficient T cell responses. In this study, we will investigate T cell responses after infection with mutated strains of influenza viruses. We will engineer a panel of mutant influenza viruses, which alter the nature and characteristics of T cells. We will analyse how efficient are these T cells and whether they can protect against a normal strain of influenza A. Subsequently, we will characterise quantitative and qualitative aspects of memory T cell pools after infection with mutant influenza viruses. Since a number of viruses such as influenza, HIV and HCV rapidly mutate their genes, our study will not only address the question of T cell responses to mutated influenza viruses, but also will provide an excellent model for investigating protective T cell responses to other viral infections.Read moreRead less
T cells are a central component of the immune system and without T cells the body is very vulnerable to infections. One subgroup of T cells is the killer T cells that are important for identifying and killing cells infected by viruses and bacteria. The immune system works to maintain T cell numbers at a fairly constant level and part of this process includes sending signals to the killer T cells from other cells via cell surface protein interactions and soluble mediators, such as cytokines. We h ....T cells are a central component of the immune system and without T cells the body is very vulnerable to infections. One subgroup of T cells is the killer T cells that are important for identifying and killing cells infected by viruses and bacteria. The immune system works to maintain T cell numbers at a fairly constant level and part of this process includes sending signals to the killer T cells from other cells via cell surface protein interactions and soluble mediators, such as cytokines. We have been studying killer T cells, which are missing a protein SOCS1. SOCS1 is important for switching off the signals generated by a group of cytokines. As a consequence of being unable to correctly regulate cytokine signals these killer T cells multiply inappropriately and contribute to disease development. Our current work is aimed at achieving a better understanding of the particular interactions between killer T cells and other immune system cells and the soluble factors that deliver important signals for maintaining killer T cells in the immune system. The ability to better understand the factors controlling the maintenance of killer T cells will enable us to more intelligently target the immune system ,which is important for improving vaccine strategies and cancer immunotherapy as well as for controlling T cells that are activated inappropriately, such as in autoimmune disease.Read moreRead less
Evaluation Of Immune Correlates For Virus-specific CD8+ T Cells Following Prime-boost Vaccination
Funder
National Health and Medical Research Council
Funding Amount
$397,889.00
Summary
This project will use cutting-edge technology to evaluate the quality of virus-specific white blood cells generated following vaccination. Clinically relevant vaccination strategies will be analysed in a well characterised mouse model of infection to produce correlates associated with protective vaccine efficacy, particularly in an immunosupressed setting. This will lead to more focused research and ultimately the development of prophylactic and therapeutic HIV vaccines.
Defining The Cellular Interactions For Initiation And Maintenance Of Immunity To Intracellular Pathogens
Funder
National Health and Medical Research Council
Funding Amount
$863,413.00
Summary
This immune system provides our body’s defense against invading organisms like viruses, preventing disease and maintaining health. Immunity involves the interaction of several different cell types that together form arsenals tailored to combat each different infection. Professor Heath will investigate how cells of the immune system orchestrate effective immune responses to viral infections and malaria. He will use this understanding to design novel approaches to vaccination.
Chromatin Remodelling And Transcriptional Regulation Of CD8 T Cell Effector Gene Expression
Funder
National Health and Medical Research Council
Funding Amount
$531,696.00
Summary
A major role for cytotoxic, or killer, T cells is the recognition and removal of virus infected or tumor cells from a host. Upon recognition of a target host cell, killer T cells deliver a package of proteins, termed granzymes, that mediate the removal of these virus infected and tumor cells. Naive killer T cells need to be activated to start producing these effector molecules. This proposal plans to examine the factors that regulate both induction and maintanence of cell specific expression of ....A major role for cytotoxic, or killer, T cells is the recognition and removal of virus infected or tumor cells from a host. Upon recognition of a target host cell, killer T cells deliver a package of proteins, termed granzymes, that mediate the removal of these virus infected and tumor cells. Naive killer T cells need to be activated to start producing these effector molecules. This proposal plans to examine the factors that regulate both induction and maintanence of cell specific expression of these effector molecules. We plan to identify the molecular events that occur within a cells genome to turn on granzyme gene expression and how these factors influence subsequent killer T cell function. The conclusions from these studies will enable us to determine why some killer T cell responses are not effective and what can be done to improve killer T cell function. This has implications for the development of novel vaccine strategies designed to induce immunity against both viral and tumour challenges.Read moreRead less
Vaccines aim to protect against future infections by inducing memory in the immune system so that the host can react quickly to the next challenge. Defence against viral infections and some cancers depends in part on activating CD8+ T cells, a class of white blood cell that can recognise and kill infected or malignant cells. The ideal vaccines against these challenges would therefore generate high numbers of long-lived CD8+ T cells that are programmed to make the right response if the infection ....Vaccines aim to protect against future infections by inducing memory in the immune system so that the host can react quickly to the next challenge. Defence against viral infections and some cancers depends in part on activating CD8+ T cells, a class of white blood cell that can recognise and kill infected or malignant cells. The ideal vaccines against these challenges would therefore generate high numbers of long-lived CD8+ T cells that are programmed to make the right response if the infection or tumour re-emerges. Little is known about the programming of memory CD8+ T cells. We have recently found that some of these cells have the potential to be reprogrammed to display different functions by exposure to new stimuli. This opens up the possibility that ineffective responses could be improved by using vaccination to control the production of these flexible or multipotential memory cells or to reprogram them once they are formed. Alternatively, effective responses might be subverted by pathogens to the detriment of the host. The goal of this project is to learn how the first exposure to an immune challenge influences the development of these multipotential memory CD8+ cells. Understanding the signals and processes that generate multipotential memory cells will be the first step towards developing ways to manipulate them to improve immune defence.Read moreRead less
The Role Of CD4+ T Cells In The Tumour Killing By CD8+ Memory T Cells.
Funder
National Health and Medical Research Council
Funding Amount
$303,000.00
Summary
It has been observed that human cancers grow in spite of the presence of tumour antigen specific memory CD8+ tumour killer T cells in the body. These memory killer cells are unable to kill the cancer. Our research work in a mouse model indicates that the CD8+ T cells can be activated to kill cancers if cancer antigen specific CD4+ T helper cells are activated. The mechanism how this happens is not clear. The role of regulatory or suppressor CD4+ T cells are also not known. In this proposal we wi ....It has been observed that human cancers grow in spite of the presence of tumour antigen specific memory CD8+ tumour killer T cells in the body. These memory killer cells are unable to kill the cancer. Our research work in a mouse model indicates that the CD8+ T cells can be activated to kill cancers if cancer antigen specific CD4+ T helper cells are activated. The mechanism how this happens is not clear. The role of regulatory or suppressor CD4+ T cells are also not known. In this proposal we wish to study the mechanism of how CD8+ memory T cells get activated to cancer killer cells by the CD4+ T helper cells. This information will help us to design better immunotherapies for cancer patients.Read moreRead less