Elucidating inhibitory signalling in T cell activation using optogenetics
Lead Research Organisation:
University of Warwick
Department Name: Warwick Medical School
Abstract
T cells are an essential part of our immune system that eliminate infections to keep us healthy despite constant exposure to pathogens. T cells contain an intricate signalling network that can identify whether the cells of our body have become infected, but sometimes this decision-making process is ineffective and leads to disease. Many current drugs are designed to manipulate these signalling pathways to improve the immune response to infection or cancer. Whilst great progress has been made in identifying the parts of these networks, we must also understand the dynamic connections between them to know how these therapies work and hopefully improve them. However, for most signalling networks this knowledge remains very limited. To address this, we develop new molecular tools to investigate the dynamics of the T cell signalling network by engineering inputs that respond to chemicals or light, giving us precise control over signalling in space and time.
In the proposed work, we will explore how inhibitory receptors expressed by T cells affect the downstream output response. It has been suggested that these inhibitory receptors only control one part of the signalling network, but this result has been hard to verify. The result has important consequences, as many of the 'checkpoint' inhibitors currently used for treatments for cancer patients target inhibitory receptors, such as PD-1, so knowing how they work at the fundamental level is required to improve their clinical function. To address this limitation, we will develop and implement new tools to investigate this hypothesis at the molecular level. We will create inhibitory receptors whose activity can be controlled by light when engaged by their ligands within their native cellular environment.
The first main objective of the proposed research is to map how the information from PD-1 receptor binding is decoded by the T cell intracellular signalling network, with the expectation of identifying parts of the signalling network that could be controlled by new drugs or therapies. Secondly, we will expand this approach to understand the mechanism of action for a diverse range of inhibitory receptors expressed by T cells, to look for common features between their function. The final objective will leverage the power of light as a cell input to 'pulse' T cell activation, which we have recently found to decrease inhibitory signalling. We will investigate how these time-varying signals are 'read' by the network, to again find parts that could be new targets for improved therapies for cancer patients.
In the proposed work, we will explore how inhibitory receptors expressed by T cells affect the downstream output response. It has been suggested that these inhibitory receptors only control one part of the signalling network, but this result has been hard to verify. The result has important consequences, as many of the 'checkpoint' inhibitors currently used for treatments for cancer patients target inhibitory receptors, such as PD-1, so knowing how they work at the fundamental level is required to improve their clinical function. To address this limitation, we will develop and implement new tools to investigate this hypothesis at the molecular level. We will create inhibitory receptors whose activity can be controlled by light when engaged by their ligands within their native cellular environment.
The first main objective of the proposed research is to map how the information from PD-1 receptor binding is decoded by the T cell intracellular signalling network, with the expectation of identifying parts of the signalling network that could be controlled by new drugs or therapies. Secondly, we will expand this approach to understand the mechanism of action for a diverse range of inhibitory receptors expressed by T cells, to look for common features between their function. The final objective will leverage the power of light as a cell input to 'pulse' T cell activation, which we have recently found to decrease inhibitory signalling. We will investigate how these time-varying signals are 'read' by the network, to again find parts that could be new targets for improved therapies for cancer patients.
Technical Summary
T cells are an essential part of our immune system and employ an intricate signalling network to decide whether the cells of our body have become infected; sometimes this decision-making process is ineffective leading to disease. Many current drugs, including checkpoint inhibitors (CPI) are designed to manipulate these signalling pathways to improve the immune response to infection or cancer. Whilst we have an excellent understanding of the parts of these networks, our knowledge of the dynamic connections between these components remains very limited. This intellectual deficit not only reduces our mechanistic understanding of T cell activation but also hinders how CPI currently used for cancer immunotherapy could be improved.
To overcome this challenge, we have pioneered the use of optogenetics to modulate both the intensity and duration of signalling from activating receptors within their native cellular context. This quantitative control allows us to directly interrogate T cell signalling dynamics for a more complete understanding of their decision-making capability. We will extend this exciting new technology to investigate inhibitory receptor function in T cells. The overall goal of the proposed work is to delineate the network architecture of inhibitory signalling in T cells, with the hypothesis that signalling from inhibitory receptors is capable of counteracting direct activation through the T cell antigen receptor as well as the costimulatory pathways, which has important consequences for how checkpoint inhibitors function therapeutically.
The main objectives are to map how the dynamic information from the engagement of a range of inhibitory receptor is decoded by the T cell intracellular signalling network. We will also define how pulsatile activating signals are decoded by the network, which we find can minimise the transition to the exhausted T cell state.
To overcome this challenge, we have pioneered the use of optogenetics to modulate both the intensity and duration of signalling from activating receptors within their native cellular context. This quantitative control allows us to directly interrogate T cell signalling dynamics for a more complete understanding of their decision-making capability. We will extend this exciting new technology to investigate inhibitory receptor function in T cells. The overall goal of the proposed work is to delineate the network architecture of inhibitory signalling in T cells, with the hypothesis that signalling from inhibitory receptors is capable of counteracting direct activation through the T cell antigen receptor as well as the costimulatory pathways, which has important consequences for how checkpoint inhibitors function therapeutically.
The main objectives are to map how the dynamic information from the engagement of a range of inhibitory receptor is decoded by the T cell intracellular signalling network. We will also define how pulsatile activating signals are decoded by the network, which we find can minimise the transition to the exhausted T cell state.
