Receptors And Ligands Regulating Human NK Cell Proliferation
Funder
National Health and Medical Research Council
Funding Amount
$692,040.00
Summary
A white blood cell called a Natural Killer (NK) cell is critical in the early control of viral infections and cancer. NK cells kill the diseased cells and secrete immunological hormones (cytokines) that alter how cells of the blood and immune systems respond. These functions of NK cells are markedly increased when NK cells are stimulated to divide. This project seeks to understand how NK cell proliferation is controlled. Receptors that recognise 'self' inhibit NK cell function and cell division ....A white blood cell called a Natural Killer (NK) cell is critical in the early control of viral infections and cancer. NK cells kill the diseased cells and secrete immunological hormones (cytokines) that alter how cells of the blood and immune systems respond. These functions of NK cells are markedly increased when NK cells are stimulated to divide. This project seeks to understand how NK cell proliferation is controlled. Receptors that recognise 'self' inhibit NK cell function and cell division thereby preserving self and destroying diseased cells. Yet many NK cells express both an inhibitory and activating receptor for this same 'self' protein. We will investigate what determines the outcome of this competing information. Many NK cell receptors remain to be identified and we will use a gene expression approach and monoclonal antibodies to identify these and determine how they affect NK cell proliferation. We will use molecular engineering to construct multimeric arrays of new NK cell receptors to search for the ligand molecules that they interact with on other cells. Identifying NK cell receptors and their ligands regulating NK cell proliferation and function will enable us to understand the role of these cells in health and in inflammatory diseases and cancer.Read moreRead less
Antigen Receptor Sharing By Lymphocytes During An Immune Response
Funder
National Health and Medical Research Council
Funding Amount
$286,328.00
Summary
A successful immune response relies on the ability of immune cells to quickly mount a specific offensive against invading foreign pathogens like bacteria or viruses. The specificity of this offensive is governed by receptors that can recognise pathogens. To survive an infection the immune system must rapidly expand the number of immune cells that have receptors that recognise, and can therefore specifically combat, the infection. The underlying theory of immunology, the clonal selection theory, ....A successful immune response relies on the ability of immune cells to quickly mount a specific offensive against invading foreign pathogens like bacteria or viruses. The specificity of this offensive is governed by receptors that can recognise pathogens. To survive an infection the immune system must rapidly expand the number of immune cells that have receptors that recognise, and can therefore specifically combat, the infection. The underlying theory of immunology, the clonal selection theory, states that this expansion is mediated by the proliferation of immune cells selected on the basis of expressing a pathogen specific receptor. We hypothesise that in addition to this proliferation the immune system may also expand the number of immune cells expressing pathogen-specific receptors by transferring these receptors between cells by a means of cell-membrane sharing. Indeed, we have evidence that this does occur both in the test tube and in animals and can function to amplify the number of immune cells that can specifically recognise a pathogen and thereby help with immune response development. This grant aims to further advance our understanding of this novel phenomenon.Read moreRead less
The Regulation Of Pleiotropic Responses By Phospho-Ser/Tyr Binary Switches Embedded In Growth Factor Receptors
Funder
National Health and Medical Research Council
Funding Amount
$349,190.00
Summary
Cells in the body are able to accomplish an impressive range of functions within their lifetime. Underlying this diversity in cellular functions are a quorum of fundamental cellular responses that include cell survival, cell proliferation (growth) and cell differentiation (commitment to a more mature cell identity). Diffusible factors (called growth factors) are important in regulating these cellular responses. This is achieved through growth factor binding to specific proteins (called receptors ....Cells in the body are able to accomplish an impressive range of functions within their lifetime. Underlying this diversity in cellular functions are a quorum of fundamental cellular responses that include cell survival, cell proliferation (growth) and cell differentiation (commitment to a more mature cell identity). Diffusible factors (called growth factors) are important in regulating these cellular responses. This is achieved through growth factor binding to specific proteins (called receptors) on the surface of cells which in turn activate signalling cascades that convey messages within the cell instructing a specific response. We have identified a new mechanism that allows a growth factor receptor to convert analogue inputs (in the form of growth factor stimulation) to a digital output (where a cell responds in a decisive fashion). This analogue-to-digital conversion is encoded by a molecular switch embedded in growth factor receptors that toggles between two alternate positions to promote either cell survival alone or cell survival as well as cell differentiation-proliferation. In this manner, these molecular switches have binary (either-or) characteristics and provide a new explanation for the independent regulation and coordination of different cell functions. These findings have implications for understanding how specific cellular responses such as cell survival, proliferation and differentiation can be regulated and perhaps harnessed to improve tissue regeneration after damage (e.g. in stroke, heart attack trauma) or in understanding how things go wrong in diseases such as cancer where cell survival, proliferation and differentiation become deregulatedRead moreRead less