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This application seeks information on the factors controlling T cell survival, tolerance and responsiveness to foreign antigens and tumour antigens. Particular attention will be directed to determining how T cells are kept alive through contact with self ligands and cytokines while preserving self tolerance and how anti-tumour responses can improved without augmenting the function of T regulatory cells.
CD8+ T cells provide us with protection against viruses and can also mediate potent anti-tumour effects. Understanding the signals that initiate and sustain an effective CD8+ T cell response is important if we are to intervene in diseases where CD8+ T cell function is defective. We will study patients with inherited gene defects that disrupt some of the signals that T cells receive to determine the role those signals usually play in instructing CD8+ T cells to fight viral infection.
CCR9 Expressing T Helper Cells In Immunity And Autoimmunity
Funder
National Health and Medical Research Council
Funding Amount
$729,571.00
Summary
We have identified a unique subset of immune cells in autoimmune lesions named Tccr9 cells. You find these cells in the gut, but when the body shifts into disease mode, Tccr9 cells disseminate to the accessory organs of the digestive system. Understanding the relationship between gut Tccr9 cells and the Tccr9 cells that contribute to chronic inflammation and autoimmunity is the focus of this research proposal.
Our bodies rely on the production of potent, or ‘high affinity’, antibodies to fight infection. We have found that antibody responses are unexpectedly boosted following the depletion of a specific subset of immune cells. This is especially true for B cells that are poor antibody producers. Our findings are likely to be relevant to (1) the design of vaccines to infectious agents that have important CTL and antibody components (e.g. HIV), (2) for the improved production of antibody for therapeutic ....Our bodies rely on the production of potent, or ‘high affinity’, antibodies to fight infection. We have found that antibody responses are unexpectedly boosted following the depletion of a specific subset of immune cells. This is especially true for B cells that are poor antibody producers. Our findings are likely to be relevant to (1) the design of vaccines to infectious agents that have important CTL and antibody components (e.g. HIV), (2) for the improved production of antibody for therapeutic use (e.g. cancer).Read moreRead less
Immunoregulation Of Subsets Of Memory CD8+ T Cells
Funder
National Health and Medical Research Council
Funding Amount
$233,867.00
Summary
Information will be sought on the properties of T cells, a class of white blood cells that play a vital role in combating infectious agents. Using mouse models, subsets of T cells that carry immunological memory will be studied and assessed for their rate of cell division and dependence on soluble messengers known as cytokines and other stimuli. The data will provide useful knowledge on the causes of autoimmune diseases (such as rheumatoid arthritis, type 1 diabetes and lupus) and help in the de ....Information will be sought on the properties of T cells, a class of white blood cells that play a vital role in combating infectious agents. Using mouse models, subsets of T cells that carry immunological memory will be studied and assessed for their rate of cell division and dependence on soluble messengers known as cytokines and other stimuli. The data will provide useful knowledge on the causes of autoimmune diseases (such as rheumatoid arthritis, type 1 diabetes and lupus) and help in the development of successful second generation vaccines.Read moreRead less
Lipid Antigen Recognition By Diverse CD1-restricted T Cells
Funder
National Health and Medical Research Council
Funding Amount
$312,625.00
Summary
Natural Killer T (NKT) cells are a specialized T cell lineage that form a key part of the adaptive immune response required for protection against infection, allergy, cancer and autoimmune diseases. Different types of NKT cells exist, expressing distinct T cell receptors that recognize a large array of lipid antigens presented during disease conditions. Understanding the mechanisms involved in lipid recognition is crucial in deciphering how NKT cells can be manipulated for desired immune respons ....Natural Killer T (NKT) cells are a specialized T cell lineage that form a key part of the adaptive immune response required for protection against infection, allergy, cancer and autoimmune diseases. Different types of NKT cells exist, expressing distinct T cell receptors that recognize a large array of lipid antigens presented during disease conditions. Understanding the mechanisms involved in lipid recognition is crucial in deciphering how NKT cells can be manipulated for desired immune responses.Read moreRead less
Understanding the factors that control T cell responses has been a major focus of immunology. Despite this effort the factors that control T cell development, homeostasis and function are still only incompletely understood. Accordingly we have been studying the TNF-family cytokine BAFF (B cell activation factor of the TNF-family) in relation to T cell behaviour and function. Though BAFF was first described as being critical for B cell development and maturation, a number of lines of evidence ind ....Understanding the factors that control T cell responses has been a major focus of immunology. Despite this effort the factors that control T cell development, homeostasis and function are still only incompletely understood. Accordingly we have been studying the TNF-family cytokine BAFF (B cell activation factor of the TNF-family) in relation to T cell behaviour and function. Though BAFF was first described as being critical for B cell development and maturation, a number of lines of evidence indicate that BAFF may be important in T cell biology. Current studies suggest that BAFF exerts a pro-inflammatory effect upon T cell responses. Surprisingly then, when we examined the role of BAFF upon T cell function in vivo in the context of the allo-immune response, we found that ~60% of BAFF transgenic mice failed to reject a fully-mismatched allograft. Intriguingly, BAFF transgenic mice exhibited an increased number of CD4+ CD25+ Foxp3+ cells in the periphery and in vivo depletion of these CD25+ cells restored the ability of BAFF transgenic mice to reject an allograft. We hypothesize that BAFF plays a potentially powerful anti-inflammatory role in regulating certain T cell dependent immune responses. Our data suggests that BAFF can modulate T cell function by effecting T cell regulation.Read moreRead less
The Importance Of GM-CSF In Determining The Fate And Function Of Dendritic Cell (DC) Subsets: Resident DC, Inflammatory DC And Suppressive DC.
Funder
National Health and Medical Research Council
Funding Amount
$334,053.00
Summary
The hormone GM-CSF determines how infections are seen by the immune system GM-CSF is a hormone already in use for increasing the production of white blood cells. We have found that it also affects their function, especially that of specialised white blood cells that process infectious materials to be recognised by the immune system. This project aims to detail the effects of GM-CSF on specialised white blood cells.
Cytokine Production By Human Dendritic Cells - Is Less More?
Funder
National Health and Medical Research Council
Funding Amount
$378,107.00
Summary
Dendritic cells (DC) are specialist white blood cells responsible for initiating and coordinating immune responses against pathogens and cancer. DC act as sentinels of the immune system and are found throughout the body where they are in constant surveillance for infections or danger signals. Once armed they traffic to the lymph nodes, where they activate T lymphocytes and NK cells, which are then responsible for mounting an attack against the infection or tumour. The complex mechanisms of how d ....Dendritic cells (DC) are specialist white blood cells responsible for initiating and coordinating immune responses against pathogens and cancer. DC act as sentinels of the immune system and are found throughout the body where they are in constant surveillance for infections or danger signals. Once armed they traffic to the lymph nodes, where they activate T lymphocytes and NK cells, which are then responsible for mounting an attack against the infection or tumour. The complex mechanisms of how dendritic cells respond to danger, and how they direct T and NK cells to induce specific immune responses appropriate for a particular infection are poorly understood. Most of our current knowledge of DC has been obtained from mouse studies, and it is believed that secretion of cytokines by dendritic cells play an important role. Human dendritic cells have been difficult to identify, however we have pioneered methods to isolate and characterise them from human tissue. We will therefore investigate the production of cytokines from human DC subsets and the role they play in the induction of immune responses. DC can be instructed in the test tube to recognise a cancer and mount an immune response, and this is a promising new therapy for cancer. Our work will uncover fundamental information about the most potent danger signal, the type of DC and the most important cytokines for inducing immune responses against cancers, and will therefore assist in the development of cancer vaccines.Read moreRead less