Elucidation of the transcriptional programme of memory T cells by a systems approach
Lead Research Organisation:
University College London
Department Name: Institute of Child Health
Abstract
This project aims to reveal the fundamental molecular mechanisms of immunological memory at the gene level. Immunological memory is a unique attribute of the adaptive immune system and provides extremely efficient defense against pathogens. Because the immune system has this capacity, humans and animals (including mammals, birds, and fish) can efficiently eradicate life-threatening pathogens, especially viruses, that were once encountered in the past or for which they were immunised. Thus, immunological memory is essential for maintaining health and longevity, and the control of immunological memory will provide a mean for improving the prevention and treatment of infectious diseases, and for developing effective vaccines against pathogens such as HIV. It is, however, still unclear how immunological memory is determined and maintained in the immune system.
This study aims to reveal how immunological memory is provided by lymphocytes, especially in T cells. T cells coordinate the activities of other immune cells, and generate efficient and rapid responses to pathogens. Thus, not surprisingly, some viruses such as HIV target T cells, and thereby cause the major symptoms of acquired immune deficiency syndrome (AIDS). Memory T cells may play central roles both in immunity to pathogens and on vaccination. Research on memory T cells, however, has been difficult and will require multiple approaches, including immunology, molecular biology, and systems biology.
Thus, we will employ an integrated approach of immunology, molecular biology, genomics, and systems biology, and address how immunological memory is maintained in memory T cells at the gene level. Immunological and molecular approaches will identify which of already known molecules are involved in generation and function of memory T cells. Genomics will identify new molecular mechanisms for controlling memory T cells. The systems approach will identify the complex regulatory mechanisms between the molecules and thereby provide rigid frameworks to fully discover the mechanisms of the generation and function of memory T cells. These together will reveal the critical mechanisms that underlie T cell memory, which can then be exploited for the development of new immunosuppressive drugs and vaccine designs.
The project is designed to swiftly transfer knowledge and technology to industry, including the pharmaceutical industry. The understanding of the mechanism of T cell memory at the gene level is important not only for scientific progress but also for patency and for the development of new immunosuppressive drugs and vaccines. We also aim to use the findings of the project to improve the efficiency of the screening processes in the development of new drugs. The combined approach of experiments and mathematical modelling in this study can be directly used for screening processes for immunomodulative drugs, which can contribute to improve the cost performance of drug development at the preclinical stage.
This study is highly multidisciplinary. The applicant is an immunologist and molecular biologist, and has recently trained for genomics and systems biology. With this background, the applicant will coordinate collaborations with mathematical modellers, statisticians, and immunologists to provide the most efficient answers to this problem. The findings of this study will benefit broad scientific communities and contribute to health and well-being of humans and animals. In addition, this study will provide novel frameworks for systems biology, which can be used in many biological areas.
This study aims to reveal how immunological memory is provided by lymphocytes, especially in T cells. T cells coordinate the activities of other immune cells, and generate efficient and rapid responses to pathogens. Thus, not surprisingly, some viruses such as HIV target T cells, and thereby cause the major symptoms of acquired immune deficiency syndrome (AIDS). Memory T cells may play central roles both in immunity to pathogens and on vaccination. Research on memory T cells, however, has been difficult and will require multiple approaches, including immunology, molecular biology, and systems biology.
Thus, we will employ an integrated approach of immunology, molecular biology, genomics, and systems biology, and address how immunological memory is maintained in memory T cells at the gene level. Immunological and molecular approaches will identify which of already known molecules are involved in generation and function of memory T cells. Genomics will identify new molecular mechanisms for controlling memory T cells. The systems approach will identify the complex regulatory mechanisms between the molecules and thereby provide rigid frameworks to fully discover the mechanisms of the generation and function of memory T cells. These together will reveal the critical mechanisms that underlie T cell memory, which can then be exploited for the development of new immunosuppressive drugs and vaccine designs.
The project is designed to swiftly transfer knowledge and technology to industry, including the pharmaceutical industry. The understanding of the mechanism of T cell memory at the gene level is important not only for scientific progress but also for patency and for the development of new immunosuppressive drugs and vaccines. We also aim to use the findings of the project to improve the efficiency of the screening processes in the development of new drugs. The combined approach of experiments and mathematical modelling in this study can be directly used for screening processes for immunomodulative drugs, which can contribute to improve the cost performance of drug development at the preclinical stage.
This study is highly multidisciplinary. The applicant is an immunologist and molecular biologist, and has recently trained for genomics and systems biology. With this background, the applicant will coordinate collaborations with mathematical modellers, statisticians, and immunologists to provide the most efficient answers to this problem. The findings of this study will benefit broad scientific communities and contribute to health and well-being of humans and animals. In addition, this study will provide novel frameworks for systems biology, which can be used in many biological areas.
Technical Summary
The memory response is the key feature of immunological memory, where the immune system responds to antigens in a more rapid and efficient way than during the primary response. T cells are central to such adaptive responses, and memory T cells show a more rapid and efficient response upon antigenic stimulation. It is, however, still obscure how memory T cells are generated by encounter with pathogens, and how memory T cells efficiently respond to antigens and propagate activation through interacting with other T cells and antigen-presenting cells. In addition, currently memory T cells lack specific markers and can be identified only by the expression of a set of markers or their situation, which hampers the analysis of the dynamic response of memory T cells.
The major objectives of this study are to understand T cell memory as a network of proteins/genes or as a cell population, by a systems approach using time course analysis and mathematical modelling: (1) analysis of the gene regulatory mechanisms of T cell activation-related molecules in memory T cells during the memory response; (2) analysis of the propagation of the activation from memory T cells through the naive T cell pool. The dynamics of the activation of T cells will be analysed at single cell level. This will identify physiological memory T cell populations; (3) identification of the transcriptional regulations that are specific to memory T cells by time course analysis of these cells during the memory response using a novel framework of microarray analysis with a multidimensional technique. These three stand-alone approaches will elucidate the mechanisms at different levels of T cell memory, and together strengthen the biological relevance of this study. In addition, these will define memory T cells and thereby provide the basis for future studies and applications. In addition, the modelling and multidimensional frameworks to analyse memory T cells can be used in other areas of biology.
The major objectives of this study are to understand T cell memory as a network of proteins/genes or as a cell population, by a systems approach using time course analysis and mathematical modelling: (1) analysis of the gene regulatory mechanisms of T cell activation-related molecules in memory T cells during the memory response; (2) analysis of the propagation of the activation from memory T cells through the naive T cell pool. The dynamics of the activation of T cells will be analysed at single cell level. This will identify physiological memory T cell populations; (3) identification of the transcriptional regulations that are specific to memory T cells by time course analysis of these cells during the memory response using a novel framework of microarray analysis with a multidimensional technique. These three stand-alone approaches will elucidate the mechanisms at different levels of T cell memory, and together strengthen the biological relevance of this study. In addition, these will define memory T cells and thereby provide the basis for future studies and applications. In addition, the modelling and multidimensional frameworks to analyse memory T cells can be used in other areas of biology.
Planned Impact
The project will benefit the following groups and thereby contribute to human well-being and health, and enhance the economic competitiveness of the UK.
1) Pharmaceutical industry
The project will contribute to pharmaceutical industry by providing drug targets as well as screening methods for candidate compounds. First, the molecular mechanism of memory T cells will provide targets for immunoregulatory drugs. Second, the combined system of experiments and theories that will be established in the project can be used at the preclinical stage of development of immunosuppressive drugs. We plan to start collaborations with pharmaceutical industry and aim to realise these benefits within 2-10 years thereafter.
2) Biotechnological industry
The antibodies to key molecules in T cell memory will be widely used in immunology and related areas and their commercialisation will benefit the biotechnological industry. I will use my informal connections with biotechnological companies, starting collaborations with them in the lifetime of the project and aiming to realise these benefits within 1-3 years thereafter.
3) Immunisation practice and vaccine development
The monoclonal antibodies or molecular markers for memory T cells can be used for monitoring the effectiveness of immunisation, which will optimise immunisation plans. In addition, elucidation of the mechanisms of T cell memory will provide molecular targets for boosting the immune system, which can be exploited for vaccine development. These collectively will benefit public and global health and vaccine industry.
4) Governmental policy in public health regarding immunisation
The project will provide a modern understanding of the mechanisms of immunisation, which will make the governmental policy more effective in providing new plans for immunisation. We will liaise with the Research Council to transfer our knowledge to policy communities. This will be done within the lifetime of the project.
5) General Public
The project will benefit the health and the quality of life of the general public via three pathways: (a) improved healthcare service (see 6); (b) improved immunisation practice (see 3); and (c) in-depth understanding of immunisation. We will hold workshops to convey the frontline understanding of immunisation through educating pupils, which will improve their uptake of necessary vaccines at proper timings. We will publish the contents of these workshop to influence broad audience.
6) Health service
The project will contribute to improve health practice via three pathways. First, the findings of this project will promote studies in related clinical research areas to elucidate the molecular mechanism of immunity against pathogens. Second, the proposed project will identify drug target for controlling memory T cells to enhance immunity in aged people. The realisation of these benefits will be within 2- 10 years after the completion of the proposed project. Third, we will rapidly disseminate our findings to health and public health professionals by publishing our perspectives in medical journals for the successful development of the health service section.
7) Animal health
The project will contribute to improve health practice of animals, and thereby contribute to animal welfares, farming, and food production via three pathways: (i) effective development of vaccines (see 3); (ii) prevention and treatment of infectious disease including zoonosises. The realisation of these benefits will be within 2- 10 years after the completion of the proposed project.
8) Education and training of scientists
The project will nurture the involved post-doc and students to have a high quality research capacity by providing a wide range of skills and knowledge of experiments, modelling, and data analysis and their integration.
1) Pharmaceutical industry
The project will contribute to pharmaceutical industry by providing drug targets as well as screening methods for candidate compounds. First, the molecular mechanism of memory T cells will provide targets for immunoregulatory drugs. Second, the combined system of experiments and theories that will be established in the project can be used at the preclinical stage of development of immunosuppressive drugs. We plan to start collaborations with pharmaceutical industry and aim to realise these benefits within 2-10 years thereafter.
2) Biotechnological industry
The antibodies to key molecules in T cell memory will be widely used in immunology and related areas and their commercialisation will benefit the biotechnological industry. I will use my informal connections with biotechnological companies, starting collaborations with them in the lifetime of the project and aiming to realise these benefits within 1-3 years thereafter.
3) Immunisation practice and vaccine development
The monoclonal antibodies or molecular markers for memory T cells can be used for monitoring the effectiveness of immunisation, which will optimise immunisation plans. In addition, elucidation of the mechanisms of T cell memory will provide molecular targets for boosting the immune system, which can be exploited for vaccine development. These collectively will benefit public and global health and vaccine industry.
4) Governmental policy in public health regarding immunisation
The project will provide a modern understanding of the mechanisms of immunisation, which will make the governmental policy more effective in providing new plans for immunisation. We will liaise with the Research Council to transfer our knowledge to policy communities. This will be done within the lifetime of the project.
5) General Public
The project will benefit the health and the quality of life of the general public via three pathways: (a) improved healthcare service (see 6); (b) improved immunisation practice (see 3); and (c) in-depth understanding of immunisation. We will hold workshops to convey the frontline understanding of immunisation through educating pupils, which will improve their uptake of necessary vaccines at proper timings. We will publish the contents of these workshop to influence broad audience.
6) Health service
The project will contribute to improve health practice via three pathways. First, the findings of this project will promote studies in related clinical research areas to elucidate the molecular mechanism of immunity against pathogens. Second, the proposed project will identify drug target for controlling memory T cells to enhance immunity in aged people. The realisation of these benefits will be within 2- 10 years after the completion of the proposed project. Third, we will rapidly disseminate our findings to health and public health professionals by publishing our perspectives in medical journals for the successful development of the health service section.
7) Animal health
The project will contribute to improve health practice of animals, and thereby contribute to animal welfares, farming, and food production via three pathways: (i) effective development of vaccines (see 3); (ii) prevention and treatment of infectious disease including zoonosises. The realisation of these benefits will be within 2- 10 years after the completion of the proposed project.
8) Education and training of scientists
The project will nurture the involved post-doc and students to have a high quality research capacity by providing a wide range of skills and knowledge of experiments, modelling, and data analysis and their integration.
People |
ORCID iD |
Masahiro Ono (Principal Investigator / Fellow) |
Publications
Bending D
(2016)
255 Foxp3 activation within effector T-cells controls the antigen-specific T-cell response in the contact hypersensitivity model
in Journal of Investigative Dermatology
Sahni H
(2015)
A genome wide transcriptional model of the complex response to pre-TCR signalling during thymocyte differentiation.
in Oncotarget
Bending D
(2018)
A temporally dynamic Foxp3 autoregulatory transcriptional circuit controls the effector Treg programme.
in The EMBO journal
Bending D
(2018)
A timer for analyzing temporally dynamic changes in transcription during differentiation in vivo.
in The Journal of cell biology
Sinclair C
(2015)
A Zap70-dependent feedback circuit is essential for efficient selection of CD4 lineage thymocytes
in Immunology & Cell Biology
Jennings E
(2021)
Application of dual Nr4a1-GFP Nr4a3-Tocky reporter mice to study T cell receptor signaling by flow cytometry
in STAR Protocols
Ono M
(2016)
Controversies concerning thymus-derived regulatory T cells: fundamental issues and a new perspective.
in Immunology and cell biology
Description | The project investigates how a special type of white blood cells, T cells, respond to external stimulation and 'memorise' it. To this end, the project has developed a completely new experimental tool to analyse how individual respond to stimulation and control immune response in the body. This is done by using a unique fluorescent protein that changes colour spontaneously. Thus, by analysing the colour of the protein in isolated T cells, we can investigate how individual cells responded to stimulation in the body. This is a groundbreaking technology, and can be used in a wide range of academic and industrial studies. |
Exploitation Route | Our studies have established an innovative tool and thereby improved the understanding of how T cells memorise the stimulations that they once encountered (e.g. infections). It is expected that the tool and new knowledge will further improve the understanding of how the immune system works, and promote studies on infection, vaccination, and cancer immunotherapy, benefiting pharmaceutical and biotech industries and human health. |
Sectors | Agriculture, Food and Drink,Healthcare,Pharmaceuticals and Medical Biotechnology |
Description | Attentions from the general public through news, Twitter and blog sites - proved by high Altmetric scores (119), https://jcbrupress.altmetric.com/details/44115098/news |
First Year Of Impact | 2018 |
Sector | Healthcare |
Impact Types | Societal |
Description | BBSRC Impact Acceleration Account 2015-2016 |
Amount | £14,909 (GBP) |
Funding ID | 4020012831 |
Organisation | Biotechnology and Biological Sciences Research Council (BBSRC) |
Sector | Public |
Country | United Kingdom |
Start | 11/2015 |
End | 06/2016 |
Description | CRCE pump priming collaborative pilot project grant |
Amount | £29,913 (GBP) |
Organisation | Imperial College London |
Sector | Academic/University |
Country | United Kingdom |
Start | 09/2017 |
End | 08/2018 |
Description | Development of vaccine for gastrointestinal nematode parasite of livestock |
Amount | £40,257 (GBP) |
Organisation | Biotechnology and Biological Sciences Research Council (BBSRC) |
Sector | Public |
Country | United Kingdom |
Start | 12/2016 |
End | 03/2017 |
Description | Elucidating molecular and cellular mechanisms underlying T-cell dysfunction and effective anti- cancer T-cell responses: towards the development of next-generation immunotherapy |
Amount | £1,548,151 (GBP) |
Funding ID | DCRPGF\100007 |
Organisation | Cancer Research UK |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 11/2021 |
End | 10/2027 |
Description | Facility usage at the University of Tokushima, Japan |
Amount | ¥500,000 (JPY) |
Organisation | University of Tokushima |
Sector | Academic/University |
Country | Japan |
Start | 09/2016 |
End | 03/2017 |
Description | Repurposing computational tools to evaluate anti-cancer immunity for development of cancer immunotherapy |
Amount | £21,476 (GBP) |
Organisation | Engineering and Physical Sciences Research Council (EPSRC) |
Sector | Public |
Country | United Kingdom |
Start | 10/2016 |
End | 03/2017 |
Title | Multidimensional genomic analysis method |
Description | A novel multidimensional genomic analysis method has been developed to investigate the function and differentiation of T cell subsets at genomics level by adapting a multidimensional method, Canonical Correspondence Analysis (CCA), to genomics analysis. |
Type Of Material | Technology assay or reagent |
Year Produced | 2014 |
Provided To Others? | Yes |
Impact | The method has been used in 5 publications from my collaborators. |
Title | Canonical Correspondence Analysis |
Description | We have adapted Canonical Correspondence Analysis to analyse immunological genomic data including microarray and RNA-sequencing data. |
Type Of Material | Data analysis technique |
Year Produced | 2014 |
Provided To Others? | Yes |
Impact | The data analysis tool has been used by the following publications: Kenefeck et al, J Clin Inv, 2015; Sahni et al, Oncotarget, 2015; Sinclair et al, Immunol Cell Biol, 2015. |
URL | http://bmcgenomics.biomedcentral.com/articles/10.1186/1471-2164-15-1028 |
Description | Julie Josse |
Organisation | Agrocampus Ouest |
Department | Laboratory of Applied Mathematics Agrocampus (LMA) |
Country | France |
Sector | Academic/University |
PI Contribution | To lead a collaborative project, providing experimental data and performing data analysis. |
Collaborator Contribution | To provide statistical knowledge. |
Impact | One publication (Fujii et al, J Immunol, 2016). We have applied for a BBSRC funding with Julie Josse in Agrocampus Ouest as a collaborator. |
Start Year | 2013 |
Description | Reiko J Tanaka |
Organisation | Imperial College London |
Department | Department of Bioengineering |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | To lead a collaborative project, provide experimental data and data anlaysis. |
Collaborator Contribution | To provide mathematical analysis. |
Impact | With Dr Reiko J Tanaka in the organisation as a co-PI, I have been awarded a BBSRC IAA. The collaboration is multi-disciplinary involving immunology, molecular biology, mathematical modelling, multidimensional data analysis. |
Start Year | 2013 |
Description | Immuno-dancing |
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 | Immuno-dancing: I have established a novel way to convey immunology to primary school pupils by combining immunology with dancing (which I have named Immuno-dancing). The session is composed of two activities: (1) 14~15 pupils dance in a ring, and thereby become a big macrophage, which is a special immune cell dedicated for eating germs; (2) to learn Division of Labour of the immune system. We make 3 groups (dendritic cells, B cells, macrophages), and each of which has 5-6 pupils. The roles are given to each groups, to understand how immune cells coordinate an immune response. We have done the Immuno-dancing in a local primary school with a great success, and will continue developing the method. |
Year(s) Of Engagement Activity | 2016,2018 |
Description | Immunology workshop for primary school 2018 |
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 | We delivered a workshop for immunological memory and vaccination to a primary school (St Clemant Danes CoE primary school, London). |
Year(s) Of Engagement Activity | 2018 |
Description | Powys Dance CELL Project |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Other audiences |
Results and Impact | On behalf of Imperial's Outreach Department, I have been collaborating with a Welsh dance company (Powys Dance) for the production of the show CELL DANCE. We have given scientific inputs to the choreographer, dancers, music composer, and inflatable artist. The show will visualise (1) the research life and lab; (2) cells; (3) T cell response; and DNA and chromatin. The first show will be at Imperial in July 2019, and Powys Dance will do a tour in Wales. We will also produce a website (will be hosted by Imperial) to provide scientific backgrounds to children and teachers. Furthermore, we are preparing to produce a comic for the show. The impact is so far ~10 artists involved (since the show is still being prepared) but after the release of website and the tour, we expect that we can reach more than 500 people. |
Year(s) Of Engagement Activity | 2018 |