| Co-Investigator(Kenkyū-buntansha) |
RAJEWSKY Klaus Institute for Genetics, University of Cologne, 遺伝研, 教授
LEDERMAN Seth College of Physicians & Surgeons of Columbia University, 医学部, 助教授
CLARK Edward A School of Medicine, University of Washington, 医学部, 教授
KONDO Shigeru Postgraduate School of Medicine, Kyoto University, 医学研究科, 講師 (10252503)
KOHSAKA Hitoshi Medical Research Institute, Tokyo Medical and Dental University, 難治疾患研究所, 助手 (00251554)
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| Research Abstract |
We have assessed the regulatory mechanisms for B cell apoptosis and differentiation by T cells and follicular dendritic cells. For this purpose, we first established the cellular systems in which apoptosis of lined B cells is regulated by lined T cells or FDC,or defined molecules derived from these cells. Indeed, the B cell line WEHI-231 was rescued from antigen receptor-mediated apoptosis by either lined FDC or T cells expressing CD40L.Since FDC cells did not express ligands for CD40, FDC may rescue WEHI-231 cells by CD40-independent mechanisms. Moreover, CD40 signaling but not FDC induced expression of anti-apoptotic molecules, Bcl-2 and Bcl-x, suggesting that FDC rescues WEHI-231 cells by distinct mechanisms from CD40 signaling. In other studies, we found that the cyclin-dependent kinase inhibitor p27^<Kip1>, which negatively regulate cell cycle progression, is upregulated by antigen receptor signaling and down modulated by CD40 signaling in WEHI-231. When we cultured WEHI-231 in th
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e presence of the antisense oligonucleotides for p27^<Kip1>, WEHI-231 failed to undergo apoptosis upon antigen receptor crosslinking, suggesting that p27^<Kip1> is an important target molecule of CD40 signaling for B cell survival.
We also established the cellular system in which molecular mechanisms for immunoglobulin class switching, a crucial step of B cell differentiation, can be assessed. We established a subclone (F3) of CH12 B lymphoma cells which undergo class switching frm IgM to IgA efficiently in the presence of CD40 ligand, IL-4 and TGF-beta. In these cells, Demethylation but not germline transcription of the C region of the immunoglobulin correlates to the efficiency of class switching. This result suggests that demethylation but not germ line transcription may play a role in class switching. To identify the molecules involved in class switching, we isolated two genes specifically expressed in F3 cells treated with CD40 ligand, IL-4 and TGF-beta. Functions of these genes are to be determined. Less
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