c-Rel is essential for B lymphocyte survival and cell cycle progression

c-Rel is a lymphoid-specific member of the NF-kappa B/Rel family of transcr iptional factors. To investigate the role of c-Rel in B lymphocyte function , we generated a c-Rel(-/-) mouse via a gene targeting approach. Although e arly lymphocyte development is normal in c-Rel(-/-) mice, there are signifi cantly fewer B cells displaying a memory (IgM/IgD(-)) phenotype. Upon immun ization, c-Rel(-/-) mice generate fewer B cells with a germinal center (PNA (hi)) phenotype. In vitro, c-Rel(-/-) B cells proliferate poorly upon ligat ion of their surface IgM or CD40 receptors or when stimulated with either l ipopolysaccharide (LPS) or T cell help. Early molecular events that precede proliferation, such as increases in RNA synthesis as well as IL-2 receptor cc chain expression, are greatly diminished in c-Rel(-/-) B cells. Further more, c-Rel(-/-) B cells are impaired in the ability to receive survival si gnals generated by anti-IgM or LPS. in contrast, CD40-mediated cell surviva l is normal in c-Rel(-/-) B cells, suggesting the involvement of a survival -signaling pathway that is independent of c-Rel. When c-Rel (-/-) B cells a re co-stimulated with either anti-IgM and CD40 or LPS and CD40, they are re ndered capable of progressing through the cell cycle. Finally, cc-culture e xperiments suggest that the defects observed in c-Rel(-/-) B cells are intr insic to the cell and can not be rescued through either cell-cell contact o r addition of soluble factors. Thus, c-Rel is requisite for differentiation to the germinal center and memory B cells in vivo and is required for the transduction of survival and cell cycle progression signals mediated by ant i-IgM and LPS in vitro. Furthermore, while c-Rel is involved in CD40-induce d proliferation, it is apparently dispensable for the survival signals tran sduced by CD40.