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

Chen, Hui-Chen
http://rave.ohiolink.edu/etdc/view?acc_num=osu1061213266

Abstract Details

2003, Doctor of Philosophy, Ohio State University, Medical Microbiology and Immunology.
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 bacterial lipopolysaccharide, a B cell mitogen, results in time dependent phosphorylation of CREB-1 at Ser 119/133 . 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 over expressing a dominant negative Ser 119-ala phosphomutant CREB-1 (mCREB-1) in B cells were generated. Analysis of these mice revealed reduced B220+IgM+ mature 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. Over expression 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 the S phase. More importantly, the transgenic pre-BII B cells failed to enter S phase in response to stimulation with IL-7 in vitro . 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 suggesting a role for CREB-1 in T-dependent immune responses. 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 to neither the defective bone marrow cells nor fetal liver cells. Interestingly, the transgenic mice revealed decreased B1a B cell population in the spleen. Consistent with the increased B1 B cells, the mutant CREB-1 transgenic mice revealed increased serum IgM levels compared to wild type control littermates. These studies provide the first evidence of a role for CRE binding proteins in the differential regulation of B1 and B2 B cell development and functional maturation.
Natarajan Muthusamy (Advisor)
Health Sciences, Immunology
CREB-1; B lymphocytes; B1 B cells; B2 B cells; Immune response; B cell development

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Citations

  • Chen, H.-C. (2003). Role for cyclic adenosine monophosphate (cAMP) response element binding proteins in B lymphocyte development and functional maturation [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1061213266

    APA Style (7th edition)

  • Chen, Hui-Chen. Role for cyclic adenosine monophosphate (cAMP) response element binding proteins in B lymphocyte development and functional maturation. 2003. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1061213266.

    MLA Style (8th edition)

  • Chen, Hui-Chen. "Role for cyclic adenosine monophosphate (cAMP) response element binding proteins in B lymphocyte development and functional maturation." Doctoral dissertation, Ohio State University, 2003. http://rave.ohiolink.edu/etdc/view?acc_num=osu1061213266

    Chicago Manual of Style (17th edition)

osu1061213266
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© 2003, all rights reserved.
This open access ETD is published by The Ohio State University and OhioLINK.