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 - Basic Medicine (Core Departments) - Immunology and Genomic Medicine
Immunology and Genomic Medicine
Contributed Chairs
We have been studying molecular mechanisms controlling development and function of lymphocytes. Currently we are addressing two important questions: 1) How antibody diversity is controlled by AID, a putative RNA-editing enzyme required for class switch recombination (CSR) and somatic hypermutation (SHM), 2) How PD-1 deficiency leads to development of autoimmune diseases.

  Tasuku Honjo, M.D., Ph.D.
Professor
Research and Education
“The mechanism of antibody memory”
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.


Immunology and Genomic Medicine
Professor Tasuku Honjo
Associate
 Professor


Nasim Begum,
Maki Kobayashi
Assistant
 Professor


Shunsuke Chikuma
TEL +81-75-753-4371
FAX +81-75-753-4388
e-mail Honjomfour.med.kyoto-u.ac.jp
URL http://www2.mfour.med.
kyoto-u.ac.jp/E_Home.htm
Recent Publications
1. Muramatsu, M., Kinoshita, K., Fagarasan, S., Yamada, S., Shinkai, Y. and Honjo, T. “Class switch recombination and hypermutation require activation-induced cytidine deaminase (AID), a potential RNA editing enzyme.” Cell (2000) 102(5):553-63.
2. Muramatsu, M., Nagaoka, H., Shinkura, R., Begum, N. A. and Honjo, T. “Discovery of activation-induced cytidine deaminase, the engraver of antibody memory.” Adv. Immunol. (2007) 94:1-36.
3. Kobayashi, M., Aida, M., Nagaoka, H., Begum, N. A., Kitawaki, Y., Nakata, M., Stanlie, A., Doi, T., Kato, L., Okazaki, I., Shinkura R., Muramatsu, M., Kinoshita, K. and Honjo, T. “AID-induced decrease in topoisomerase 1 induces DNA structural alteration and DNA cleavage for class switch recombination.” Proc. Natl. Acad. Sci. USA (2009) 106:22375-80.
4. Stanlie, A., Aida, M., Muramatsu, M., Honjo, T. and Begum, N. A. “Histone3 lysine4 trimethylation regulated by the facilitates chromatin transcription complex is critical for DNA cleavage in class switch recombination.” Proc. Natl. Acad. Sci. USA (2010) 107: 22190-5.
5. Wei, M., Shinkura, R., Doi, Y., Maruya, M., Fagarasan, S. and Honjo, T. “Knock-in mice carrying a somatic hypermutation-defective Aicda mutation have impaired gut homeostasis and compromised mucosal defense.” Nat. Immunol. (2011) 12: 264-70.
Class Switch Recombination research group

 
 
 
 
 
 
 


 
 
 
 
AID engraves antibody memory on the genome
 
 

 
 

 
 
 
 
 
PD-1 research group
PD-1 deficient mice develop autoimmune neuropathy due to the breakage of lymphocyte tolerance