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
Antigen Dose And TCR Repertoire In CD8+ T Cell Immunodominance Hierarchies
Funder
National Health and Medical Research Council
Funding Amount
$558,920.00
Summary
The CD8+, or killer , T lymphocytes (white blood cells) are the hit men of immunity, recirculating continually around the body to eliminate other cells that are dangerous because they are cancerous or infected with a virus. A major difficulty is that killer T cells also exert selective pressures that cause viruses and tumours to mutate and thus avoid immune control. This is a particularly serious problem for RNA viruses that readily mutate as they divide. These include the human immunodeficiency ....The CD8+, or killer , T lymphocytes (white blood cells) are the hit men of immunity, recirculating continually around the body to eliminate other cells that are dangerous because they are cancerous or infected with a virus. A major difficulty is that killer T cells also exert selective pressures that cause viruses and tumours to mutate and thus avoid immune control. This is a particularly serious problem for RNA viruses that readily mutate as they divide. These include the human immunodeficiency virus (HIV) that causes AIDS and, while the mutations that are most important with influenza viruses are those that modify viral surface proteins recognized by antibodies, such T cell escape mutants can also be a problem with influenza. The other reason why there is particular interest in promoting CD8+ T cell-mediated immunity to influenza is that the killer T cells are very cross-reactive. We have shown that vaccination approaches that prime mouse CD8+ T cells to resist influenza A viruses circulating currently in humans will also protect against the highly lethal, and dangerous H5N1 bird 'flu. The present flu vaccines only stimulate antibodies, so there is interest in the possibility of a major re-design. The CD8+ T cells recognize tiny elements (peptides) of the virus or tumour bound in the tip of our own transplantation, or class I major histocompatibility complex (MHCI) molecules. These pMHCI complexes are called epitopes. The focus here is on the use of novel genetic engineering strategies to find out how, when the virus mutates to disrupt the major epitopes seen by killer T cells, other minor epitopes can be abnormally emphasized in a way that promotes effective immune control. As we work on this with the relatively simple and safe influenza model we will concurrently develop strategies that may be of value in HIV and tumour immunity. Solving this problem could prove to be a substantial advance in the design of vaccines and immunotherapy approaches.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.
Memory CD4 T Cells That Harbour The Reservoir Of Latent HIV Infection: Their Antigen Specificity, Function And Frequency Of Antigen-driven Reactivation
Funder
National Health and Medical Research Council
Funding Amount
$453,782.00
Summary
Current antiretroviral therapy for HIV successfully suppresses virus production, but does not completely eliminate the virus from the body. This project will provide essential information on memory CD4 T cells that retain HIV in a latent DNA form. Memory CD4 T cells can be very long-lived, and these latently infected memory cells can give rise to virus during treatment interruption. We will use a novel method to identify which memory CD4 T cells contain latent HIV DNA.
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
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.
The Generation Of HSV-1 Specific Effector And Memory CD4+ T Cell Responses.
Funder
National Health and Medical Research Council
Funding Amount
$460,509.00
Summary
This proposal aims to determine the mechanisms underpinning the generation of helper T cell responses following HSV-1 infection. It will determine the factors that allow T cells to access sites of viral replication and the mechanisms by which they provide protection from skin infections.
Characterisation Of An Antigen Presenting Cell Unique To Spleen
Funder
National Health and Medical Research Council
Funding Amount
$420,606.00
Summary
The body depends on a range of defence mechanisms to remove invaders that enter by various routes. Antigen presenting cells are central to immunity in that they engulf and destroy dead cells and pathogens and present pieces of those pathogens or 'antigens' to white blood cells called T and B lymphocytes. These cells then start to fight the infection or disease. A new type of antigen presenting cell will be investigated for its particular ability to arrest blood-borne pathogens and disease.
Systematically Exploring The Contribution Of Immunoproteasome To Immunodominance And T Cell Function
Funder
National Health and Medical Research Council
Funding Amount
$499,860.00
Summary
Vaccine will help us to fight both infectious diseases and malignancy. However, there are few successful vaccines for infectious agents and there is simply no vaccine to cure any tumor at the moment. So, it is essential for us to learn the basics related to vaccine development. Killer T cells eliminate tumour cells or virally infected host cells by recognising fragments (epitopes) derived from tumour- or virus-derived proteins displayed on a host molecule called MHC. Normally multiple epitopes a ....Vaccine will help us to fight both infectious diseases and malignancy. However, there are few successful vaccines for infectious agents and there is simply no vaccine to cure any tumor at the moment. So, it is essential for us to learn the basics related to vaccine development. Killer T cells eliminate tumour cells or virally infected host cells by recognising fragments (epitopes) derived from tumour- or virus-derived proteins displayed on a host molecule called MHC. Normally multiple epitopes are generated as part of the protein recycling program referred as proteine degradation which is mainly conducted by bundled enzyme complex, called proteasome. Two major forms of proteasomes are expressed by most cells. One called house-keeping proteasome and the other, which replaces the house-keeping one during viral infections is called immunoproteasome. The role that the immunoproteasome plays during anti-viral and anti-tumoral immune responses is not fully understood. In addition, the immunoproteasome is also expressed by a few cell types that do not suppose to need it if its function is entirely to generate better epitopes for MHC to display. In this project, we will sytematically explore the contribution of the immunoproteasome to overall anti-viral and anti-tumoral immune responses in three mouse model systems. The shared feature of these systems is that multiple killer T cell epitopes have been defined, which could potentially provide us with very sensitive assessments. The three systems are anti-influenza, anti-vaccinia virus and anti-tumor antigen (NY-ESO-1) mouse models.Read moreRead less
Investigations Into The Biology And Functionality Of The Human T Cell Receptor
Funder
National Health and Medical Research Council
Funding Amount
$424,262.00
Summary
T lymphocytes play a pivotal role in the immune system by recognising virus-infected tissue and tumour cells through the use of specific cell surface receptors called T cell receptors (TCR). This project will study why partcular TCRs are used by the immune system, and will also examine the specificity of T cell recognition by determine the range of molecules an individual T cell can recognise. The work will aid in the development of new intelligent vaccines for cancer and infectious disease.