Understanding And Modulating The Human Immune System
Funder
National Health and Medical Research Council
Funding Amount
$470,144.00
Summary
T cells are the sentinels of our immune system continually scanning our tissue for abnormalities and eliminating threats in many forms. They are our second and last line of defence against microorganisms and cancer. Unfortunately, T cells can also cause harm through accidental crossreactvity or overzealous function. My work is directed at understanding how T cells work and how they can be controlled using drugs and gene therapy. If we can ‘tune’ the power of this master immune lineage we can unl
Interleukin Signalling In CD4+ T Cell Differentiation
Funder
National Health and Medical Research Council
Funding Amount
$663,919.00
Summary
Our bodies rely on the production of antibodies to fight infection. The cytokine IL-21 is produced by immune cells called T follicular helper (Tfh) cells that help B cells make antibodies. Tfh cells, in turn, are controlled by regulatory (Tfr) cells. Our findings demonstrate that IL-21 supports Tfh cells and limits Tfr cells, thus favoring antibody production and long term immunity. Using genomic and cellular approaches, the mechanism(s) underlying these observations will be explored.
Professor Godfrey is an immunologist with a long standing history as a pioneer in the study of a specialised type of white blood cell, known as NKT cells. NKT cells are activated in response to lipid-based molecules that are thought to alert the immune system, via NKT cell activation, to the presence of infectious agents or other abnormalities. A better understanding of how NKT cells function will provide new approaches to battling a broad range of diseases where these cells are implicated, incl ....Professor Godfrey is an immunologist with a long standing history as a pioneer in the study of a specialised type of white blood cell, known as NKT cells. NKT cells are activated in response to lipid-based molecules that are thought to alert the immune system, via NKT cell activation, to the presence of infectious agents or other abnormalities. A better understanding of how NKT cells function will provide new approaches to battling a broad range of diseases where these cells are implicated, including cancer, autoimmunity, allergy and infection.Read moreRead less
Extracellular Cues Compete With TCR Signalling To Alter Lymphocyte Polarity, Fate And Function.
Funder
National Health and Medical Research Council
Funding Amount
$509,954.00
Summary
Following an infection, our immune system generates a large and diverse repertoire of cells required to mount and regulate an appropriate immune response. The signals that control the different types of immune cells that develop, and how bacteria and viruses influence immune cell development, are not fully understood. This project will investigate the regulation of immune cell development, and how competing signals from infectious agents influence this process.
Cytotoxic T Lymphocyte Synapse Formation And Serial Killing: When Breaking Up Is Hard To Do.
Funder
National Health and Medical Research Council
Funding Amount
$626,688.00
Summary
Killer T cells are a specialised group of immune cells, which destroy cancerous and infected cells. When killer T cells find a target, they attach and secrete toxic molecules. It then detaches from the dying target, so that it may go on to kill other cells. If it doesn’t detach properly, it remains bound to the target cell and results in an improper immune response. This proposal will investigate how the killer cell detaches, which is essential for an efficient immune response.
Investigating CD4+ T Helper Cell Differentiation During Blood-stage Plasmodium Infection
Funder
National Health and Medical Research Council
Funding Amount
$408,388.00
Summary
Some infections tend to afflict us only once, e.g. chickenpox, because our bodies develop immunity to these microbes relatively easily. In contrast, it takes many infections to develop immunity to the malaria parasite, because our immune systems seem to respond inefficiently to it. My work will improve our understanding of how the immune system is poorly activated during malaria, and may provide new ideas for boosting the immune system in response to malaria or indeed other infections.
The Phenotype Of Protective Cytotoxic T Cell Responses During Viral Infections
Funder
National Health and Medical Research Council
Funding Amount
$841,114.00
Summary
T cell responses are important to establish protection against pathogens and some cancer via generation of memory cells that can be maintained long term and defeat promptly re-infections. This proposal aim at determining important factors that drive the success of immunological memory by employing single cell technologies and unique longitudinal samples from subjects infected with hepatitis C virus. The finding of this study will inform current vaccine research and immunotherapies.
The Role Of C-Cbl In The Regulation Of T Cell Signalling And Development
Funder
National Health and Medical Research Council
Funding Amount
$527,250.00
Summary
c-Cbl is a member of a multi-adaptor protein family that can interact with many signalling proteins via its different domains. Cbl proteins have been implicated as negative regulators of signalling pathways involving protein tyrosine kinases (PTKs). PTKs are enzymes which add phosphate groups to tyrosine residues on other protein substrates, and the process of tyrosine phosphorylation acts as a potent biochemical switch to turn signalling cascades on and off. Studies of Cbl-deficient (knockout) ....c-Cbl is a member of a multi-adaptor protein family that can interact with many signalling proteins via its different domains. Cbl proteins have been implicated as negative regulators of signalling pathways involving protein tyrosine kinases (PTKs). PTKs are enzymes which add phosphate groups to tyrosine residues on other protein substrates, and the process of tyrosine phosphorylation acts as a potent biochemical switch to turn signalling cascades on and off. Studies of Cbl-deficient (knockout) mice show that Cbl proteins are important in regulating the development of, and signalling by, cells of the immune system called T cells. c-Cbl knockout mice show greatly enhanced PTK-signalling responses and deregulated activity of a PTK called ZAP-70. The mechanism of this is not known, but analysis of a c-Cbl mutant mouse shows that this is not dependent on the tyrosine kinase binding (TKB) domain of c-Cbl. Therefore other functional domains of Cbl must be responsible for the increased signalling response in the c-Cbl knockout mouse. One candidate is the highly conserved RING finger domain which can modify Cbl-associated PTKs by addition of ubiquitin molecules. Ubiquitination of a protein often, but not always, leads to its degradation, and this could be how Cbl controls the strength and duration of signalling in T cells. However there may be other functions of the conserved RING finger yet to be identified. c-Cbl itself is prominently and very rapidly modified by tyrosine phosphorylation on tyrosine 737 by the Fyn PTK following T cell activation, but the role of this modification is not known and could also be essential for c-Cbl s function in T cells. We plan to investigate the roles of the RING finger domain and Fyn-mediated tyrosine phosphorylation in c-Cbl regulation of T cell signalling by analyzing knock-in mice that carry specific mutations disrupting the RING finger or tyrosine 737 in the c-Cbl gene.Read moreRead less
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.