An investigation into CD1a, a versatile antigen-presenting molecule. This project aims to investigate how T lymphocytes are activated by lipids presented by the skin-associated antigen-presenting molecule, CD1a. Using X-ray crystallography and cellular immunology, we will provide fundamental insight into this poorly understood immunological axis. We will determine the molecular basis for how CD1a presents diverse self and foreign lipids, and how such CD1a-lipid complexes are recognised by the r ....An investigation into CD1a, a versatile antigen-presenting molecule. This project aims to investigate how T lymphocytes are activated by lipids presented by the skin-associated antigen-presenting molecule, CD1a. Using X-ray crystallography and cellular immunology, we will provide fundamental insight into this poorly understood immunological axis. We will determine the molecular basis for how CD1a presents diverse self and foreign lipids, and how such CD1a-lipid complexes are recognised by the responding T cells. This basic science discovery project will provide substantial new knowledge in the burgeoning field of lipid-mediated immunity, which should ultimately lead to new therapies targeting the CD1a lipid display molecule to either prevent immune mediated damage or promote protective immunity as required.Read moreRead less
Investigating the evolution of innate and adaptive cellular immunity. This proposal aims to assess the impact of geographical and genetic isolation of the Australian Indigenous population on adaptive and innate immune systems. The project will use novel DNA sequencing approaches to generate the high resolution sequences of two genetic loci that regulate innate and adaptive immune responses, the major histocompatibility complex locus and the killer cell immunoglobulin-like receptor locus. In an i ....Investigating the evolution of innate and adaptive cellular immunity. This proposal aims to assess the impact of geographical and genetic isolation of the Australian Indigenous population on adaptive and innate immune systems. The project will use novel DNA sequencing approaches to generate the high resolution sequences of two genetic loci that regulate innate and adaptive immune responses, the major histocompatibility complex locus and the killer cell immunoglobulin-like receptor locus. In an initial screen, distinct variants and combinations of these genes were identified. This project aims to interrogate how variation in these critical genes impacts on the function of cytotoxic lymphocytes, providing insights into the evolutionary drivers of immune recognition mechanisms.Read moreRead less
Redefining the immune landscape of the human ocular surface. At the ocular surface, the cornea and limbus need to mount effective immune responses to maintain corneal transparency for clear vision. The current paradigm is that the human cornea houses the same innate immune cell subsets (dendritic cells and macrophages) as naïve mice in pathogen-free facilities. Our pilot data challenge this premise, with early evidence that innate and adaptive cells (T cells) coexist in normal human corneas. Int ....Redefining the immune landscape of the human ocular surface. At the ocular surface, the cornea and limbus need to mount effective immune responses to maintain corneal transparency for clear vision. The current paradigm is that the human cornea houses the same innate immune cell subsets (dendritic cells and macrophages) as naïve mice in pathogen-free facilities. Our pilot data challenge this premise, with early evidence that innate and adaptive cells (T cells) coexist in normal human corneas. Integrating state-of-the-art techniques, we will advance understanding of immune regulation at the human ocular surface by comprehensively defining immune cell biology and dynamics. We will define the effect of age on immune cells in these tissues, and relationships between the tear proteome and cell behaviours.Read moreRead less
Defining the microenvironmental regulators of spleen function and immunity. The spleen is an important organ that is present in almost all vertebrates and is a critical site for the induction of systemic immune responses. The current paradigms of spleen biology are mostly derived from rodent studies, but the cellular biology of the spleen in humans remains poorly defined. Using novel tools, advanced transcriptomics and imaging techniques this project aims to reveal the functions of stromal cells ....Defining the microenvironmental regulators of spleen function and immunity. The spleen is an important organ that is present in almost all vertebrates and is a critical site for the induction of systemic immune responses. The current paradigms of spleen biology are mostly derived from rodent studies, but the cellular biology of the spleen in humans remains poorly defined. Using novel tools, advanced transcriptomics and imaging techniques this project aims to reveal the functions of stromal cells in the spleen in humans and to define the fundamental roles of spleen stromal cells in long-lived immunity. The anticipated outcomes are to build Australia’s research capacity and to generate new knowledge of significance for our fundamental understanding of the spleen and the role of this tissue in the immune system.Read moreRead less
Atypical T cell receptor recognition of monomorphic CD1 antigen-presenting molecule. T lymphocytes are white blood cells that respond to foreign molecules (antigens). Until recently, most known antigens were proteins. This project will study how T lymphocytes recognise a different class of antigen (glycolipids) that are likely to play an equally important role in the immune system.
Understanding the life and death of Mucosal-associated invariant T cells. Cell death of naïve T cells in lymphoid organs is well-understood. However, T cells only gain their function upon activation, and how activated T cells regulate their life or death remains unclear. Mucosal-associated Invariant T (MAIT) cells are abundant in non-lymphoid tissues as key local players in immunity, and share some features of activated conventional T cells. This project aims to define how MAIT cell survival and ....Understanding the life and death of Mucosal-associated invariant T cells. Cell death of naïve T cells in lymphoid organs is well-understood. However, T cells only gain their function upon activation, and how activated T cells regulate their life or death remains unclear. Mucosal-associated Invariant T (MAIT) cells are abundant in non-lymphoid tissues as key local players in immunity, and share some features of activated conventional T cells. This project aims to define how MAIT cell survival and death are controlled. It combines methods we developed to track MAIT cells in vivo with expertise in cell death analysis. This project is expected to elucidate the complex mechanisms controlling MAIT cell survival/death and increase our fundamental understanding of cell death mechanisms of activated T cells.Read moreRead less
Understanding the diverse biology of CD4+ T cell resident memory. This project aims to examine the biology of CD4 T cell memory in tissues. The previously unappreciated complexity of the CD4 T cell resident memory compartment in the liver will be characterised, focusing on the generation, maintenance and diversity of functions of these cells. Expected outcomes include the generation of fundamental knowledge in the disciplines of cellular biology and immunology, and unique, highly specialised stu ....Understanding the diverse biology of CD4+ T cell resident memory. This project aims to examine the biology of CD4 T cell memory in tissues. The previously unappreciated complexity of the CD4 T cell resident memory compartment in the liver will be characterised, focusing on the generation, maintenance and diversity of functions of these cells. Expected outcomes include the generation of fundamental knowledge in the disciplines of cellular biology and immunology, and unique, highly specialised student and personnel training through the interdisciplinary approach utilised, which spans cellular biology, live-imaging and transcriptomic analyses. Expected benefits include influential publications and the import of a novel, specialised technique to Australia through an international collaboration (Germany)Read moreRead less
Unrestricted antigen recognition by T lymphocytes. This project aims to investigate the unrestricted T cell repertoire; the molecular and structural basis of antigen recognition by unrestricted T cells; and the development of unrestricted T cells. T lymphocytes typically are restricted to detecting foreign molecules (antigens) on the cell membrane in association with specialised antigen-presenting molecules encoded within the highly polymorphic major histocompatibility (MHC) locus (MHC restricti ....Unrestricted antigen recognition by T lymphocytes. This project aims to investigate the unrestricted T cell repertoire; the molecular and structural basis of antigen recognition by unrestricted T cells; and the development of unrestricted T cells. T lymphocytes typically are restricted to detecting foreign molecules (antigens) on the cell membrane in association with specialised antigen-presenting molecules encoded within the highly polymorphic major histocompatibility (MHC) locus (MHC restriction). T lymphocytes that can recognise antigens in the absence of MHC or MHC like molecules challenges a major paradigm in the field of immunology. As T cell based therapy underpins treatments for cancer and infection, new mechanisms of T cell activation that are independent of patient genotype should ultimately create opportunities for therapeutic and commercial development, leading to both health and economic benefits.Read moreRead less
Deciphering novel cross-talk between innate cytokine receptors. Understanding the basic functions of interferons, how they signal to cells, is central to understanding fundamental immunity. Interferons are crucial molecules of the immune system that are important for normal cell development and they protect the body from viral infection and cancer but can be deleterious in different autoimmune diseases and trauma settings. Preliminary Data shows there is a pathway of interferon signalling that h ....Deciphering novel cross-talk between innate cytokine receptors. Understanding the basic functions of interferons, how they signal to cells, is central to understanding fundamental immunity. Interferons are crucial molecules of the immune system that are important for normal cell development and they protect the body from viral infection and cancer but can be deleterious in different autoimmune diseases and trauma settings. Preliminary Data shows there is a pathway of interferon signalling that has previously been overlooked. This project aims to understand how this pathway works and how it contributes to the normal workings of cells. This fundamental science has future consequences for the design of vaccines and for the design of therapeutics to treat diseases that show defective interferon signalling.Read moreRead less
The molecular basis of T cell receptor cross-reactivity between MHC and MR1. This project aims to investigate how newly discovered immune cells, known as 'MR1T' cells, function in the body. Preliminary evidence shows that MR1T cells can kill stressed cells. This project expects to generate new knowledge describing precisely how MR1T cells target and kill stressed cells. Expected outcomes of this project include to refine research techniques and models, foster interinstitutional collaborations, a ....The molecular basis of T cell receptor cross-reactivity between MHC and MR1. This project aims to investigate how newly discovered immune cells, known as 'MR1T' cells, function in the body. Preliminary evidence shows that MR1T cells can kill stressed cells. This project expects to generate new knowledge describing precisely how MR1T cells target and kill stressed cells. Expected outcomes of this project include to refine research techniques and models, foster interinstitutional collaborations, and further develop our theory on MR1T cell function. This project should provide significant benefits, such as publication of research articles in high impact journals and generation of experimental tools sought after by researchers in the field.Read moreRead less