Elucidation of the transcriptional programme of memory T cells by a systems approach

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.

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 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.