Transcriptional regulation of memory B cell development

Abstract

Antigen-reactive B cells in the spleen of mice immunized with T cell-dependent antigens generate antibody-producing foci in periarteriolar lymphoid sheaths (PALS) or migrate into follicles to form germinal centers. Germinal center B cells clonally expand, have somatic hypermutation in IgV-region genes, are selected by apoptosis on the basis of antigen-specific signals, and differentiate to memory B cells. Two transcription factors (Bcl6 and c-Fos) in B cells play a critical role in the development of germinal centers. (1) Bcl6 is highly expressed in germinal center B cells, and defects in B cells perturb the formation of germinal centers but not that of PALS-associated foci, indicating the essential role of Bcl6 in the differentiation. (2) Overexpression of c-Fos in germinal center B cells induces apoptosis and perturbs the formation of memory B cells. Overexpression of Bcl-2 cannot rescue c-Fos-induced apoptosis in germinal center B cells. Since c-Fos is induced in mature B cells which have reacted with antigens, and clonal deletion of self-reactive B cells is insensitive to overexpression of Bcl-2, c-Fos may play a causal role in the clonal deletion of germinal center B cells. Thus, these factors provide a unique opportunity to investigate the molecular mechanisms of memory B cell development.