Control mechanisms for B cell apoptosis and differentiation

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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 … More 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