The role of AMPK in CD8+ effector T cells.
Lead Research Organisation:
University of Dundee
Department Name: School of Life Sciences
Abstract
The aim of this project is to uncover the molecular details of how T cells adapt to and cope to the metabolic stress encountered during immune reposes. We will do this by interrogating how the energy sensing kinase adenosine monophosphate-activated protein kinase (AMPK) and the intracellular recycling mechanism autophagy influence effector T cell function.
Cytotoxic T cells (CTL) are effector lymphocytes that kill pathogen infected cells and cancer cells. However, low levels of nutrients and oxygen can inhibit effector T cell function, leading to lack of disease clearance. For example , within the tumour microenvironment metabolic competition can induce T cell hypo-responsiveness/exhaustion and consequently T cells can fail to protect against cancer.
To achieve these goals we will be generating RNASeq, proteomic and flow cytometry datasets from T cells under various conditions of metabolic stress. This will range from in-vitro derived CTL to tumour infiltrating T cells. By using mice with T cell selective deletion of AMPK to explore how AMPK influences T cell immune responses to tumours. Mice expressing a fluorescent autophagy reporter will be able to characterize CTL autophagy in both in-vitro and in-vivo models.
Combined these datasets will help us understand the impact of various metabolic stressors and the coping mechanisms T cells employ to deal with this stress from the message level through to cellular function. Greater understanding of these effects could lead to the development of potential therapeutics, targeting metabolic stress-related diseases, such as cancer.
Key Words and Skills: AMPK, Autophagy, CTL, T Cells, Proteomics, Flow cytometry, RNASeq, Tumour models, Immunometabolism, Glucose.
Questions:
1. Explain interdisciplinary interface: I work with many different techniques ranging from animal tumour models to analysing large protein databases . Learning to interact with large datasets requires skills which I have been able to obtain by going on training courses sponsored by the MRC. Without these opportunities I would not be able to analyse, understand and present my data effectively.
2. Does project require significant amount of quantitative skills? YES
3. Does project require significant amount of whole organism physiology skills? YES
Cytotoxic T cells (CTL) are effector lymphocytes that kill pathogen infected cells and cancer cells. However, low levels of nutrients and oxygen can inhibit effector T cell function, leading to lack of disease clearance. For example , within the tumour microenvironment metabolic competition can induce T cell hypo-responsiveness/exhaustion and consequently T cells can fail to protect against cancer.
To achieve these goals we will be generating RNASeq, proteomic and flow cytometry datasets from T cells under various conditions of metabolic stress. This will range from in-vitro derived CTL to tumour infiltrating T cells. By using mice with T cell selective deletion of AMPK to explore how AMPK influences T cell immune responses to tumours. Mice expressing a fluorescent autophagy reporter will be able to characterize CTL autophagy in both in-vitro and in-vivo models.
Combined these datasets will help us understand the impact of various metabolic stressors and the coping mechanisms T cells employ to deal with this stress from the message level through to cellular function. Greater understanding of these effects could lead to the development of potential therapeutics, targeting metabolic stress-related diseases, such as cancer.
Key Words and Skills: AMPK, Autophagy, CTL, T Cells, Proteomics, Flow cytometry, RNASeq, Tumour models, Immunometabolism, Glucose.
Questions:
1. Explain interdisciplinary interface: I work with many different techniques ranging from animal tumour models to analysing large protein databases . Learning to interact with large datasets requires skills which I have been able to obtain by going on training courses sponsored by the MRC. Without these opportunities I would not be able to analyse, understand and present my data effectively.
2. Does project require significant amount of quantitative skills? YES
3. Does project require significant amount of whole organism physiology skills? YES
Organisations
Studentship Projects
| Project Reference | Relationship | Related To | Start | End | Student Name |
|---|---|---|---|---|---|
| MR/N013735/1 | 05/09/2016 | 30/09/2025 | |||
| 1786139 | Studentship | MR/N013735/1 | 05/09/2016 | 31/08/2020 |
| Description | Incredible Immunology |
| Form Of Engagement Activity | Participation in an activity, workshop or similar |
| Part Of Official Scheme? | No |
| Geographic Reach | Local |
| Primary Audience | Schools |
| Results and Impact | Incredible Immunology is an event focused on helping school pupils and teachers to learn about the human immune system and the research taking place at the University of Dundee School of Life Sciences. During the event researchers and students from the Division of Cell Signalling and Immunology facilitated interactive activities at 'stands' at Arbroath High for over 120 S1 pupils and science teachers. These stands touched on topics like vaccination, herd immunity, and immune responses. My research was represented in this program of work by people learning about how effector T cell fight infections. Feedback from pupils and public showed an increased interest in science as a topic and increased familiarity with concepts and vocabulary associated with immunology. The School of Life Sciences has since been invited back to repeat the activity, and the school has also visited us on campus to take part in laboratory activities linked to the curriculum. |
| Year(s) Of Engagement Activity | 2019 |
| Description | Incredible Immunology 2019 |
| Form Of Engagement Activity | Participation in an activity, workshop or similar |
| Part Of Official Scheme? | No |
| Geographic Reach | Local |
| Primary Audience | Schools |
| Results and Impact | Incredible Immunology is an event focused on helping school pupils and teachers to learn about the human immune system and the research taking place at the University of Dundee School of Life Sciences. During the event researchers and students from the Division of Cell Signalling and Immunology facilitated interactive activities at 'stands' at Arbroath High for over 120 S1 pupils and science teachers. These stands touched on topics like vaccination, herd immunity, and immune responses. Feedback from pupils and public showed an increased interest in science as a topic and increased familiarity with concepts and vocabulary associated with immunology. The School of Life Sciences has since been invited back to repeat the activity, and the school has also visited us on campus to take part in laboratory activities linked to the curriculum. |
| Year(s) Of Engagement Activity | 2018,2019 |
| Description | Incredible Immunology 2021 |
| Form Of Engagement Activity | Participation in an activity, workshop or similar |
| Part Of Official Scheme? | No |
| Geographic Reach | Local |
| Primary Audience | Schools |
| Results and Impact | Incredible Immunology is a schools-based engagement activity put on by the Division of Cell Signalling and Immunology based in the School of Life Sciences at the University of Dundee that focuses on the crucial knowledge around immunology, vaccines and well-being. Due to the coronavirus restrictions in place in 2021 Incredible Immunology shifted focus from in-person engagement to remote. Researchers and students prepared 'resource boxes' full of books, games and other interactive activities for pupils to use in class, and others filmed and prepared an ELISA practical that teachers could use to explore practical, hands-on science. |
| Year(s) Of Engagement Activity | 2021 |