Understanding CD8beta(+) gamma/delta T cells: a novel subset of IFNgamma-secreting innate-like T cells
Lead Research Organisation:
Queen Mary University of London
Department Name: Blizard Institute of Cell and Molecular
Abstract
Gamma/delta T cells are white blood cells that get their name from expression on their cell surface of a receptor, the "gamma/delta T cell receptor (TCR)", that can recognize a multitude of different proteins and lipids. This ability to "see" the molecular world gives gamma/delta T cells capacity to make vital contributions to a range of immune responses; for example, against viral, bacterial, fungal and parasitic infections. They have also shown promising potential in the fight against cancer, with recent studies suggesting that the presence of gamma/delta T cells in tumours is an important positive prognostic indicator.
Once engaged in immune responses, gamma/delta T cells positively influence immune outcomes through abundant production of immune effector molecules called cytokines, of which interferon-gamma (IFNgamma) is particularly important. Indeed, IFNgamma-secreting gamma/delta T cells have been linked to beneficial immune responses in numerous cancer models, and in various infections in which pathogens reside inside cells (e.g. malaria and tuberculosis).
Our ongoing studies on how gamma/delta T cells develop in the thymus have allowed us to identify a completely novel type of gamma/delta T cell that has capacity to secrete abundant amounts of IFN-gamma when activated. Notably, these cells can be readily detected by a particular cell surface marker; CD8beta, and initial investigations suggest that they have interesting "innate-like" properties.
In this proposal, we plan to fully characterize these novel CD8beta-expressing gamma/delta T cells, both during their development in the thymus, and in the various tissues and organs of the body. This characterization includes their physical features, their genetic programming (i.e. the genes which control their functions), their metabolic profile (which is now recognized to be closely linked with functional potential), and their capacity to influence immune responses by production of immune effector molecules. Importantly, we also plan to investigate the capacity of these cells to fight tumours, specifically in a breast cancer model. We predict that their capacity to secrete abundant amounts of IFNgamma will allow CD8beta-expressing gamma/delta T cells to display potent anti-tumour responses.
To complement these investigations, the identification of these novel CD8beta-expressing gamma/delta T cells, with readily identifiable features, allows us to track the development of these cells in the thymus. Our work over the past decade has allowed us to construct a framework for gamma/delta T cell development, onto which we can map the stages, inputs and checkpoints through which various gamma/delta T cells traverse. This provides important insight into how these distinct gamma/delta T cell subsets acquire their effector functions, and crucially suggests mechanisms by which these cells might function in subsequent immune responses. Thus, we will study, in depth, how CD8beta-expressing gamma/delta T cells develop in the thymus. Moreover, the capacity to specifically identify the precursors of CD8beta-expressing gamma/delta T cells (with a range of features) allows us to distinguish these cells from other subsets of gamma/delta T cells that also acquire the potential to secrete IFNgamma (but to a lesser degree). Indeed, until now, all gamma/delta T cells that have capacity to secrete IFNgamma are rather lumped together as one, which we propose has tended to mask their individual properties. As we now have the means to accurately differentiate the developmental trajectories of these distinct IFNgamma-secreting T cell subsets, we expect to provide significant additional insight into the individual functional capacities of these cells in much more detail.
Once engaged in immune responses, gamma/delta T cells positively influence immune outcomes through abundant production of immune effector molecules called cytokines, of which interferon-gamma (IFNgamma) is particularly important. Indeed, IFNgamma-secreting gamma/delta T cells have been linked to beneficial immune responses in numerous cancer models, and in various infections in which pathogens reside inside cells (e.g. malaria and tuberculosis).
Our ongoing studies on how gamma/delta T cells develop in the thymus have allowed us to identify a completely novel type of gamma/delta T cell that has capacity to secrete abundant amounts of IFN-gamma when activated. Notably, these cells can be readily detected by a particular cell surface marker; CD8beta, and initial investigations suggest that they have interesting "innate-like" properties.
In this proposal, we plan to fully characterize these novel CD8beta-expressing gamma/delta T cells, both during their development in the thymus, and in the various tissues and organs of the body. This characterization includes their physical features, their genetic programming (i.e. the genes which control their functions), their metabolic profile (which is now recognized to be closely linked with functional potential), and their capacity to influence immune responses by production of immune effector molecules. Importantly, we also plan to investigate the capacity of these cells to fight tumours, specifically in a breast cancer model. We predict that their capacity to secrete abundant amounts of IFNgamma will allow CD8beta-expressing gamma/delta T cells to display potent anti-tumour responses.
To complement these investigations, the identification of these novel CD8beta-expressing gamma/delta T cells, with readily identifiable features, allows us to track the development of these cells in the thymus. Our work over the past decade has allowed us to construct a framework for gamma/delta T cell development, onto which we can map the stages, inputs and checkpoints through which various gamma/delta T cells traverse. This provides important insight into how these distinct gamma/delta T cell subsets acquire their effector functions, and crucially suggests mechanisms by which these cells might function in subsequent immune responses. Thus, we will study, in depth, how CD8beta-expressing gamma/delta T cells develop in the thymus. Moreover, the capacity to specifically identify the precursors of CD8beta-expressing gamma/delta T cells (with a range of features) allows us to distinguish these cells from other subsets of gamma/delta T cells that also acquire the potential to secrete IFNgamma (but to a lesser degree). Indeed, until now, all gamma/delta T cells that have capacity to secrete IFNgamma are rather lumped together as one, which we propose has tended to mask their individual properties. As we now have the means to accurately differentiate the developmental trajectories of these distinct IFNgamma-secreting T cell subsets, we expect to provide significant additional insight into the individual functional capacities of these cells in much more detail.
Technical Summary
Gamma/delta T cells make vital contributions to immune responses against viral, bacterial, fungal and parasitic infections. They also show potent anti-tumour capacities that are linked to robust secretion of interferon-gamma (IFN-gamma). However, despite this obvious potential for use in cancer immunotherapies, much about IFN-gamma-secreting gamma/delta T cells remains unclear. To address this, we have sought to better understand gamma/delta T cell biology from a developmental perspective. Importantly, this has led to the recent identification of a completely novel subset of EOMES-expressing "innate-like" CD8beta(+) gamma/delta T cells that have potential to secrete large amounts of IFN-gamma (compared to other gamma/delta T cell subsets).
In this proposal, we plan to fully characterize these novel CD8beta-expressing gamma/delta T cells, both in the thymus, and from various tissues of the body. This will include analysis of phenotype, genetic and metabolic programming, and effector functions. Notably, we will also investigate their anti-tumour capacities in a breast cancer model. Indeed, we predict that their potential for abundant IFNgamma secretion will endow CD8beta-expressing gamma/delta T cells with potent anti-tumour properties.
To complement these investigations, we also plan to study the thymic stages, signalling inputs and checkpoints through which these novel gamma/delta T cells develop. This will provide mechanistic insight into how these cells acquire their effector capabilities, and how these cells might function in peripheral immune responses. Moreover, the capacity to identify precursors of CD8beta-expressing gamma/delta T cells will also permit re-evaluation of the differential developmental trajectories of other subsets of IFN-gamma-secreting gamma/delta T cells, and will thus provide important understanding of the distinct effector capacities that these different cell-types bring to peripheral immune settings.
In this proposal, we plan to fully characterize these novel CD8beta-expressing gamma/delta T cells, both in the thymus, and from various tissues of the body. This will include analysis of phenotype, genetic and metabolic programming, and effector functions. Notably, we will also investigate their anti-tumour capacities in a breast cancer model. Indeed, we predict that their potential for abundant IFNgamma secretion will endow CD8beta-expressing gamma/delta T cells with potent anti-tumour properties.
To complement these investigations, we also plan to study the thymic stages, signalling inputs and checkpoints through which these novel gamma/delta T cells develop. This will provide mechanistic insight into how these cells acquire their effector capabilities, and how these cells might function in peripheral immune responses. Moreover, the capacity to identify precursors of CD8beta-expressing gamma/delta T cells will also permit re-evaluation of the differential developmental trajectories of other subsets of IFN-gamma-secreting gamma/delta T cells, and will thus provide important understanding of the distinct effector capacities that these different cell-types bring to peripheral immune settings.
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| Daniel Pennington (Principal Investigator) |