Role for cyclic adenosine monophosphate(cAMP) response element binding proteins in B lymphocyte development and functional maturation.

摘要

Cyclic adenosine 5′ monophosphate (cAMP) response element binding protein-1 (CREB-1) belongs to the CREB/ATF leucine zipper family of transcription factors. CREB-1 is expressed in pro-B, pre-B, immature and mature B cells. Activation through the antigen receptor or CD40 molecule, but not with lipopolysaccharide, results in time dependent phosphorylation of CREB-1 at Ser119/133. CREB-1 has been implicated in the regulation of antigen receptor induced B cell activation and cytokine signaling. Taken these evidences together, we hypothesized a potential role for CREB-1 in B cell development and functional maturation in vivo. To test this hypothesis, transgenic mice overexpressing a dominant negative Ser119-ala phosphomutant CREB-1 (mCREB-1) in B cells were generated. Analysis of these mice revealed reduced B220+IgM+ B cells associated with a block in pre-BI (CD43+B220 +CD24+(int)) to pre-BII (CD43+B220 +CD24++(high)) transition resulting in the accumulation of pre-BI cells and decreased pre-BII, immature and mature B cells in the bone marrow. Overexpression of either Bcl-2 or Bcl-xL transgenes in the mCREB-1 transgenic mice failed to rescue the B cell developmental defects. The decreased pre-BII B cell expansion in mCREB-1 transgenic mice is attributed to deregulated expression of c-Jun and JunB associated with decreased cell cycle entry from the G0/G1 phase to S phase. In addition to the defects in the bone marrow, the transgenic mice exhibited decreased follicular B cells in the spleen and increased B1a and B1b B cell populations in the peritoneum. Further, while exhibiting normal antibody responses to T-independent antigens, defective secondary immune responses to T dependent antigen was observed in the transgenic mice. The increasing peritoneal B cells are observed in both B1a and B1b populations. In vitro and in vivo CFSE labeling studies indicated that the increased B1 B cells were not due to altered proliferation of transgenic peritoneal B cells. Further, reconstitution analysis in recombination activation gene-2 (RAG-2) deficient recipients indicated that the increased B1 B cells in the peritoneum were attributed neither by the defective bone marrow cells nor fetal liver cells. These studies provide the first evidence for a role for CRE binding proteins in differential regulation of B1 and B2 B cell development and functional maturation.