Dissecting Apoptosis And IL-15 Dependent Homeostasis Pathways Of Natural Killer (NK) Cells
Funder
National Health and Medical Research Council
Funding Amount
$423,809.00
Summary
We will investigate how the cytokine IL-15 regulates the homeostasis of natural killer (NK) cells. NK cells are critical for immune responses against invading viruses or bacteria or upon detection of transformed cells. NK cells are primed to attack infected or transformed cells and are rapidly activated by direct interaction or by soluble signals. Knowledge of how NK cells development and how their numbers and function are controlled is paramount to understanding infectious disease immunology an ....We will investigate how the cytokine IL-15 regulates the homeostasis of natural killer (NK) cells. NK cells are critical for immune responses against invading viruses or bacteria or upon detection of transformed cells. NK cells are primed to attack infected or transformed cells and are rapidly activated by direct interaction or by soluble signals. Knowledge of how NK cells development and how their numbers and function are controlled is paramount to understanding infectious disease immunology and developing better immuno-therapies.Read moreRead less
The Cell Death Mechanisms That Control Regulatory T Cell Homeostasis
Funder
National Health and Medical Research Council
Funding Amount
$583,782.00
Summary
A central question in immunology is how to prevent destructive immune responses (e.g. autoimmune disease) and initiate productive immune responses (e.g. against cancer). A major breakthrough in this area was the discovery of special immune cells, called a Regulatory T Cells. We propose to discover the genes that determine whether these cells live and die. We will use this information to control appropriate numbers and function of Regulatory T Cells to modify the immune system.
Influence Of TCR Signals From Contact With Self-MHC Ligands On Naive T Cell Survival
Funder
National Health and Medical Research Council
Funding Amount
$418,658.00
Summary
A diverse repertoire of naive T cells constitutes a critical part of the adaptive immune system and protects hosts from various infections and cancer. T cells are stably maintained at a constant number in the periphery by mechanisms that are not clearly understood. This proposal will shed light on how the immune system preserves a diverse na�ve T cell pool able to respond against various foreign antigens, while preventing their harmful auto-reactivity to self antigens.
Defining The Immunoregulatory Function Of Roqin: A Novel Gene Essential For Preventing Autoimmunity
Funder
National Health and Medical Research Council
Funding Amount
$721,250.00
Summary
Lupus is a systemic autoimmune disease that carries significant morbidity and mortality. Virtually any organ can be affected, including kidneys, brain and blood. Lupus is the result of a breakdown in normal regulation of the immune system. Although there is clearly a significant genetic contribution to lupus, few causative genes have been found in humans with this disease. Recently, we discovered a novel mutation in a new gene (named roqin), that cases lupus in mice. Based on preliminary investi ....Lupus is a systemic autoimmune disease that carries significant morbidity and mortality. Virtually any organ can be affected, including kidneys, brain and blood. Lupus is the result of a breakdown in normal regulation of the immune system. Although there is clearly a significant genetic contribution to lupus, few causative genes have been found in humans with this disease. Recently, we discovered a novel mutation in a new gene (named roqin), that cases lupus in mice. Based on preliminary investigations and prediction based on the structure of Roqin, we suspect that this gene may be a key immune regulator. Specifically, it is likely to be involved in maintenance of immunological self-tolerance, which normally prevents development of autoimmunity. Mice carrying the Roqin mutation have an abnormality of their T cells, which causes them to be abnormally activated, divide more readily and survive for longer. Hyperactivated T cells induce B cells to proliferate and secrete antibodies against self-tissues that eventually lead to loss of platelets, kidney damage, enlarged spleen and lymph nodes, and early death. We now want to investigate precisely how Roqin causes abnormal T cell activation. The protein sequence of Roqin predicts the existence of two zinc finger domains that are highly conserved across species and play critical functions in regulating cell growth. One of the zinc fingers is a RING domain known to have a ubiquitin-ligase activity, which is known to play a crucial role in negative regulation of lymphocyte signalling, and maintenance of tolerance. The other zinc finger domain is known to be important for destabilizing mRNA of cytokines, thereby influencing communication between lymphocytes. Elucidation of this novel mechanism of disease will help understand the cause of human lupus. It will also provide clues about more specific drug therapies that might be more efficacious, and carry less toxicity than those currently available.Read moreRead less
Determining The Role Of Rel/NF-kB Transcription Factors In CD8 T Cell Homeostasis.
Funder
National Health and Medical Research Council
Funding Amount
$426,500.00
Summary
NF-kB proteins comprise a family of transcription factors that regulate key genes involved in immune responses, inflammation, cell death and proliferation. This family of proteins are potential drug targets for treatment of various diseases. How and when such inhibitors are used in clinical situations depends on understanding how and which cells of the immune system are specifically affected by the absence of NF-kB proteins. In a number of treatment settings intercurrent viral infections occur f ....NF-kB proteins comprise a family of transcription factors that regulate key genes involved in immune responses, inflammation, cell death and proliferation. This family of proteins are potential drug targets for treatment of various diseases. How and when such inhibitors are used in clinical situations depends on understanding how and which cells of the immune system are specifically affected by the absence of NF-kB proteins. In a number of treatment settings intercurrent viral infections occur frequently and therefore there is an even greater need to understand how the immune system may be affected or compromised in response to the primary treatment. This work will provide insights into the cellular and molecular mechanisms affected by the absnece of a particular NF-kB family member (NF-kB1) in CD8 T cells during normal T cell homeostasis and when challenged with viruses. What we learn from our experiments could have important implications for the development of vaccines.Read moreRead less