Discovery Early Career Researcher Award - Grant ID: DE230100084
Funder
Australian Research Council
Funding Amount
$471,754.00
Summary
Deciphering the rules of T cell residency across intestinal compartments. Tissue-resident memory T cells (TRM) are key for immune protection against infection and cancer at barrier sites including the gut. Whilst much of our understanding of gut TRM comes from studies on the small intestine, how these cells develop and function in the large intestine is unknown. Using state-of-the-art techniques and novel animal models, this project aims to (i) identify molecular pathways by which the local inte ....Deciphering the rules of T cell residency across intestinal compartments. Tissue-resident memory T cells (TRM) are key for immune protection against infection and cancer at barrier sites including the gut. Whilst much of our understanding of gut TRM comes from studies on the small intestine, how these cells develop and function in the large intestine is unknown. Using state-of-the-art techniques and novel animal models, this project aims to (i) identify molecular pathways by which the local intestinal microenvironment influences TRM development and (ii) how these pathways could modulate TRM generation specifically in the small or large intestine. The expected outcomes are to generate fundamental new knowledge that will have significance for regulation of the immune response. Read moreRead less
Discovery Early Career Researcher Award - Grant ID: DE240101101
Funder
Australian Research Council
Funding Amount
$452,077.00
Summary
Dissecting the heterogeniety of human tissue-resident memory T cells. Tissue-resident memory T cells (TRM) are key to immune protection against infection and cancer, yet dysfunctional TRM cause autoimmune disease. Whilst much of our understanding of TRM comes from animal models, how these cells work in humans is largely unknown. This project aims to define the phenotypic, functional and regulatory heterogeneity of human TRM subsets in organs like the gut, liver, and skin using a unique human org ....Dissecting the heterogeniety of human tissue-resident memory T cells. Tissue-resident memory T cells (TRM) are key to immune protection against infection and cancer, yet dysfunctional TRM cause autoimmune disease. Whilst much of our understanding of TRM comes from animal models, how these cells work in humans is largely unknown. This project aims to define the phenotypic, functional and regulatory heterogeneity of human TRM subsets in organs like the gut, liver, and skin using a unique human organ donor tissue resource. The expected outcomes are to generate fundamental new knowledge that will have significance for the development of new therapies against infectious diseases, cancer and autoimmunity.Read moreRead less
How do unconventional T cells die? Mammalian cells die via several different mechanisms, each of which is tightly controlled at a molecular level. The choice of death pathway depends on the trigger and cell type. This project will investigate the mechanisms controlling death of T cells, including conventional T cells, and unconventional T cells, such as mucosal-associated invariant T (MAIT) cells, in normal conditions and during inflammation. It combines methods we developed to study MAIT cells ....How do unconventional T cells die? Mammalian cells die via several different mechanisms, each of which is tightly controlled at a molecular level. The choice of death pathway depends on the trigger and cell type. This project will investigate the mechanisms controlling death of T cells, including conventional T cells, and unconventional T cells, such as mucosal-associated invariant T (MAIT) cells, in normal conditions and during inflammation. It combines methods we developed to study MAIT cells in vivo with expertise in cell death analysis. This project is expected to elucidate the complex mechanisms controlling T cell survival/death and increase our fundamental understanding of cell death mechanisms of activated T cells.Read moreRead less
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
Mapping the integration of T cell fate control across time and space. This project aims to apply new methods to determine how coordination of signalling complexes impacts upon the fate of cells of the adaptive immune system. It expects to determine how the context of signallng orchestrates cell fates such as differentiation, death and proliferation. The project is expected to yield an experimental and analytical platform for further investigations into a broad range of biological questions, and ....Mapping the integration of T cell fate control across time and space. This project aims to apply new methods to determine how coordination of signalling complexes impacts upon the fate of cells of the adaptive immune system. It expects to determine how the context of signallng orchestrates cell fates such as differentiation, death and proliferation. The project is expected to yield an experimental and analytical platform for further investigations into a broad range of biological questions, and to provide new knowledge of this fundamental problem. This platform should support further work that ultimately provides new models for tissue and immune cell regeneration, and new manufacturing platforms for therapies for humans and livestock, among other benefits.Read moreRead less
Understanding T cell trafficking and function during antigenic interference. Science generally studies antigenic stimulation in isolation, by measuring immunity towards antigens derived from a single pathogen. However, as mammals can harbour more than one infection at any given time, we established a model of antigenic interference using different antigens derived from two unrelated pathogens, influenza A (IAV) and Semliki Forest virus (SFV). Our data show that prior exposure to either IAV or SF ....Understanding T cell trafficking and function during antigenic interference. Science generally studies antigenic stimulation in isolation, by measuring immunity towards antigens derived from a single pathogen. However, as mammals can harbour more than one infection at any given time, we established a model of antigenic interference using different antigens derived from two unrelated pathogens, influenza A (IAV) and Semliki Forest virus (SFV). Our data show that prior exposure to either IAV or SFV greatly perturbs T cell dynamics. This proposal will study, at cellular and molecular levels, T cell trafficking, function and clonal distribution during antigenic interference, thus advance fundamental knowledge on T cell immunity during antigenic competition, and provide a new paradigm on how we research T cell immunity.Read moreRead less