Defining pathways that control T cell lifespan for long-term immunity. This project will investigate the cellular and molecular pathways regulating lifespan of tissue-resident memory T cells (Trm cells), a non-circulating T cell subset that play a crucial role in the frontline defence against infection. Significantly, how long Trm cells live is paramount to how long immunity is sustained. Using cutting-edge cellular and molecular techniques, the expected outcomes of this project include identifi ....Defining pathways that control T cell lifespan for long-term immunity. This project will investigate the cellular and molecular pathways regulating lifespan of tissue-resident memory T cells (Trm cells), a non-circulating T cell subset that play a crucial role in the frontline defence against infection. Significantly, how long Trm cells live is paramount to how long immunity is sustained. Using cutting-edge cellular and molecular techniques, the expected outcomes of this project include identification of the genes and processes that control lifespan. This should provide significant benefits in the basic knowledge of how longevity of immunity is regulated. This understanding will be useful for future immunotherapeutic applications, such as veterinary or human vaccines requiring maximal duration of immunityRead moreRead less
Discovery Early Career Researcher Award - Grant ID: DE220100185
Funder
Australian Research Council
Funding Amount
$438,712.00
Summary
Decoding the evolution of killer T cell immunity across human lifetime. The immune system is a potent weapon for protection against pathogens. T cells have a central role as their receptors monitor the body for threats. The thymus (organ) educates receptors to discriminate between healthy and infected cells. Receptor diversity and T cell strength change throughout human life. This project aims to unravel how T cells gain and lose optimal receptors and strength. The aims are to understand 1) The ....Decoding the evolution of killer T cell immunity across human lifetime. The immune system is a potent weapon for protection against pathogens. T cells have a central role as their receptors monitor the body for threats. The thymus (organ) educates receptors to discriminate between healthy and infected cells. Receptor diversity and T cell strength change throughout human life. This project aims to unravel how T cells gain and lose optimal receptors and strength. The aims are to understand 1) The role of thymic education in diversifying receptors 2) Whether gradual loss of thymic education affects receptor diversity 3) The molecular mechanisms underlying T cell strength. The project is essential for understanding how optimal T cell immunity is formed, critical if we wish to harness this to improve healthy aging.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
Deciphering the immune complexity that orchestrates T cell activation. The adaptive immune system consists of a complex cellular network that can efficiently distinguish exogenous required inputs, such as nutrients, from those that are potentially harmful like pathogens. Such ‘friend-foe’ discrimination has its molecular basis in a multitude of receptors with specificity to certain ligands. Critically, however, it is unclear how such discrimination is mechanistically regulated at the functional ....Deciphering the immune complexity that orchestrates T cell activation. The adaptive immune system consists of a complex cellular network that can efficiently distinguish exogenous required inputs, such as nutrients, from those that are potentially harmful like pathogens. Such ‘friend-foe’ discrimination has its molecular basis in a multitude of receptors with specificity to certain ligands. Critically, however, it is unclear how such discrimination is mechanistically regulated at the functional level. We have developed new and sophisticated experimental models that will allow us to systematically dissect and unfold the complexity of the adaptive immune system and address this critical knowledge gap. Expected outcomes will critically advance our general understanding of a fundamental biological principle.Read moreRead less
Whole-body analysis of human tissue-resident memory T cells. T cells provide critical immune protection against infection and cancer, and dysfunctional T cells cause autoimmune disease. Much of our understanding of T cells comes from studies of mice and how these immune cells work in humans is not fully understood. This project aims to determine how human T cells persist and function using a unique organ donor tissue resource. The expected outcomes are to generate fundamental new knowledge about ....Whole-body analysis of human tissue-resident memory T cells. T cells provide critical immune protection against infection and cancer, and dysfunctional T cells cause autoimmune disease. Much of our understanding of T cells comes from studies of mice and how these immune cells work in humans is not fully understood. This project aims to determine how human T cells persist and function using a unique organ donor tissue resource. The expected outcomes are to generate fundamental new knowledge about the regulation of the human immune response. This knowledge is critical for the development of vaccines and immunotherapies designed to harness T cell immunity.Read moreRead less
The role of immuno-exosomes in innate immunity. This project aims to determine the role of exosomes (EV) in innate immunity. Exosomes are extracellular vesicles secreted by mammalian cells that have an important biological function in intercellular communication by transferring biologically active proteins, lipids, and RNAs to neighbouring or distant cells. Following exposure to a foreign organism, cells dynamically change the protein composition of the EV they secrete. While this data supports ....The role of immuno-exosomes in innate immunity. This project aims to determine the role of exosomes (EV) in innate immunity. Exosomes are extracellular vesicles secreted by mammalian cells that have an important biological function in intercellular communication by transferring biologically active proteins, lipids, and RNAs to neighbouring or distant cells. Following exposure to a foreign organism, cells dynamically change the protein composition of the EV they secrete. While this data supports a role for EV as key players in innate immunity, a full understanding of the biological relevance of these vesicles and how they serve as a cellular defence mechanism is lacking. This project will provide significant benefits such as addressing key questions in EV biology and providing new fundamental insights into a novel and poorly understood component of the innate immune response.Read moreRead less
Discovery Early Career Researcher Award - Grant ID: DE210100705
Funder
Australian Research Council
Funding Amount
$462,948.00
Summary
Decoding the enigmatic biology of human gamma-delta T cells. The immune system surveys our body examining molecules that signal whether or not everything is ok. T cells are a central to this and use their receptors to monitor these molecular signals. A specialised subset of T cells known as gamma-delta T cells are critical to detecting infection and cancer, yet their fundamental biology is poorly understood. This project aims to unravel this elusive biology. The aims are to understand 1. The div ....Decoding the enigmatic biology of human gamma-delta T cells. The immune system surveys our body examining molecules that signal whether or not everything is ok. T cells are a central to this and use their receptors to monitor these molecular signals. A specialised subset of T cells known as gamma-delta T cells are critical to detecting infection and cancer, yet their fundamental biology is poorly understood. This project aims to unravel this elusive biology. The aims are to understand 1. The diversity in function between gamma-delta T cell subsets, and 2. The diversity in gamma-delta T cell receptors and the molecules that these receptors detect. This work is essential for understanding gamma-delta T cell immunology which is critical if we ultimately wish to harness this to improve human health.Read moreRead less
Intraepithelial lymphocyte development and function in the intestine. This study aims to better understand the homeostatic maintenance and essential repair processes in the intestine. This project will generate new knowledge of how immune cells of the intestine, known as intraepithelial lymphocytes (IELs), engage with intestinal epithelial cells, neurons and commensal microbes to promote homeostasis and repair. Expected outcomes of this project will be identification of new molecules for future ....Intraepithelial lymphocyte development and function in the intestine. This study aims to better understand the homeostatic maintenance and essential repair processes in the intestine. This project will generate new knowledge of how immune cells of the intestine, known as intraepithelial lymphocytes (IELs), engage with intestinal epithelial cells, neurons and commensal microbes to promote homeostasis and repair. Expected outcomes of this project will be identification of new molecules for future drug and vaccine development to improve gut health and vaccination in mammals. This should provide significant benefits to the Australian population and livestock industry through improved protection against cancer, intestinal infections and increased productivity. 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