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The use of vaccination to prevent infectious diseases has made profound and enduring impacts on human welfare since it was pioneered by Jenner in 1796. Extensive studies on immunoglobulin structure and function established that effective vaccination depends on the generation of antigen-specific antibody ‘memory’ characterized by two modifications of the immunoglobulin, namely class switching in the heavy-chain constant region, and an increased affinity for antigen in the variable region.
In 1978, we proposed and subsequently proved that class switch is mediated by recombination with dynamic excision of genomic fragments. In 2000, we discovered activation-induced cytidine deaminase (AID), which is responsible for DNA cleavage to initiate both CSR and SHM. Surprisingly, AID mutates not only the antibody gene, but also protooncogenes. Whether or not AID induced in non-lymphoid cells by viral infection causes genomic alterations leading to cancer is a big question in the field. We have recently found that topoisomerase 1 (Top1) is the enzyme that initiates CSR and SHM by cleaving S and V region, respectively. In addition, AID reduces the amount of Top1, inducing the target DNA structural change, which causes the irreversible cleavage by Top1. Furthermore, the transcription coupled nucleosomal reassembly is critical for this Top1-mediated DNA cleavage during CSR and SHM.
Furthermore, we also investigate the function of Programmed cell-death-1 (PD-1), which was isolated in this laboratory and shown to be the key molecule in regulation of lymphocyte activity including tolerance. PD-1 plays critical roles in anti-cancer immunity and autoimmunity. The aim of our research is to contribute to human welfare through regulation of immune responses, elucidation of tumorigenesis and its prevention by studying the function of AID and PD-1. In our lab, highly motivated students and postdocs are collaboratively working to elucidate fundamental questions in immunology. We educate them to be independent and sophisticated scientists who are not only specialized in biochemical and immunological experimental techniques, but also have global view of life science.
Tasuku Honjo is well known for his discovery of activation-induced cytidine deaminase (AID) that is essential for class switch recombination and somatic hypermutation. AID is the enzyme that engraves antibody memory on the genome. He has established the basic conceptual framework of class switch recombination starting from discovery of DNA deletion (1978) and S regions (1980), followed by elucidation of the whole mouse immunoglobulin heavy-chain locus. His contribution further extended to cDNA cloning of IL-4 and IL-5 cytokines involved in class switching and IL-2 receptor alpha chain.
Aside from class switching recombination, he discovered PD-1 (program cell death 1), a negative coreceptor at the effector phase of immune response and showed that PD-1 modulation contributes to treatments of viral infection, tumor and autoimmunity. In addition, he is known to be a discoverer of RBP-J, a nuclear protein that interacts with the intracellular domain of Notch in the nucleus. Notch/RBP-J signaling has been shown to regulate a variety of cell lineage commitment including T and B cells.
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