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

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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.