Transcriptional Profiling of Antigen-Dependent Murine B Cell Differentiation and Memory Formation

Institute of Stem Cell Biology and Regenerative Medicine, Stanford Cancer Center, Stanford University School of Medicine, Stanford, CA 94305, USA.
The Journal of Immunology (Impact Factor: 4.92). 12/2007; 179(10):6808-19. DOI: 10.4049/jimmunol.179.10.6808
Source: PubMed

ABSTRACT Humoral immunity is characterized by the generation of Ab-secreting plasma cells and memory B cells that can more rapidly generate specific Abs upon Ag exposure than their naive counterparts. To determine the intrinsic differences that distinguish naive and memory B cells and to identify pathways that allow germinal center B cells to differentiate into memory B cells, we compared the transcriptional profiles of highly purified populations of these three cell types along with plasma cells isolated from mice immunized with a T-dependent Ag. The transcriptional profile of memory B cells is similar to that of naive B cells, yet displays several important differences, including increased expression of activation-induced deaminase and several antiapoptotic genes, chemotactic receptors, and costimulatory molecules. Retroviral expression of either Klf2 or Ski, two transcriptional regulators specifically enriched in memory B cells relative to their germinal center precursors, imparted a competitive advantage to Ag receptor and CD40-engaged B cells in vitro. These data suggest that humoral recall responses are more rapid than primary responses due to the expression of a unique transcriptional program by memory B cells that allows them to both be maintained at high frequencies and to detect and rapidly respond to antigenic re-exposure.

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    • "In summary, retrovirally transduced KLF2 leads to increased levels of the cell cycle inhibitor proteins p21 and p27 and decreased levels of c-myc, resulting in a severe block of pre-BCR-induced proliferation. KLF2 is expressed in mature, resting B cells, downregulated in activated B cells and reexpressed in memory B cells [17], [18], [19], [20]. Retroviral transduction of LPS-stimulated primary splenic B cells with KLF2 resulted in inhibition of LPS-induced activation. "
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    ABSTRACT: Maturation as well as antigen-dependent activation of B cells is accompanied by alternating phases of proliferation and quiescence. We and others have previously shown that Krüppel-like factor 2 (KLF2), a regulator of T cell quiescence and migration, is upregulated in small resting precursor (pre)-B cells after assembly of the immature pre-B cell receptor (pre-BCR) and is downregulated upon antigen-induced proliferation of mature B cells. These findings suggest that KLF2, besides its function in maintaining follicular B cell identity, peripheral B cell homeostasis and homing of antigen-specific plasma cells to the bone marrow, also controls clonal expansion phases in the B cell lineage. Here, we demonstrate that enforced expression of KLF2 in primary pre-B cells results in a severe block of pre-BCR-induced proliferation, upregulation of the cell cycle inhibitors p21 and p27 and downregulation of c-myc. Furthermore, retroviral KLF2 transduction of primary B cells impairs LPS-induced activation, favors apoptosis and results in reduced abundance of factors, such as AID, IRF4 and BLIMP1, that control the antigen-dependent phase of B cell activation and plasma cell differentiation. Hence, we conclude that KLF2 is not only a key player in terminating pre-B cell clonal expansion but also a potent suppressor of B cell activation.
    PLoS ONE 05/2014; 9(5):e97953. DOI:10.1371/journal.pone.0097953 · 3.23 Impact Factor
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    • "Their study suggests that the changes in gene expression profiles are surprisingly shared between memory B cells, memory T cells and long-term hematopoietic stem cells, suggesting a common molecular mechanism of self-renewal in all cases. Similarly, Bhattacharya et al.71 examined the transcription profiles of mouse naïve, GC, memory B cells and plasma cells. They showed increased expression of AID, chemotactic receptors, co-stimulatory molecules and several anti-apoptotic genes in memory B cells. "
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    ABSTRACT: Acquired immunological memory is a striking phenomenon. A lethal epidemic sweeps through a naïve population, many die but those who survive are never "attacked twice - never at least fatally", as the historian Thucydides observed in 430 BCE. Antibody memory is critical for protection against many human infectious diseases and is the basis for nearly all current human vaccines. Antibody memory is encoded, in part, in isotype-switched immunoglobulin (Ig)G-expressing memory B cells that are generated in the primary response to antigen and give rise to rapid, high-affinity and high-titered antibody responses upon challenge with the same antigen. How IgG-B-cell receptors (BCRs) and antigen-induced IgG-BCR signaling contribute to memory antibody responses are not fully understood. In this review, we summarize exciting new advances that are revealing the cellular and molecular mechanisms at play in antibody memory and discuss how studies using different experimental approaches will help elucidate the complex phenomenon of B-cell memory.Cell Research advance online publication 20 May 2014; doi:10.1038/cr.2014.65.
    Cell Research 05/2014; 24(6). DOI:10.1038/cr.2014.65 · 12.41 Impact Factor
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    • "We first confirmed that wild type Kras is strongly expressed in murine B-lineage cells; naïve splenic B-cells, germinal center B-cells, memory B-cells and plasma cells from C57BL/6 mice (Figure 2A) [25]. As expected, Cre-mediated excision of the Kras allele stop cassette was robust and specific to B-lineage cells undergoing class-switch recombination in vitro (Figure 2B and Figure S1). "
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    ABSTRACT: Activating mutations in Ras (N- and K-) are the most common point mutations found in patients with multiple myeloma (MM) and are associated with poor clinical outcome. We sought to directly examine the role of Ras activation in MM pathogenesis and used two different tissue-specific Cre recombinase mouse lines (Cγ1-Cre and AID-Cre), to generate mice with mutant Kras (Kras(G12D) ) activated specifically in germinal center B-cells. We also generated mice with activation of the Kras(G12D) allele in a tumor-prone Arf-null genetic background. Surprisingly, we observed no significant disruption in B-cell homeostasis in any of these models by serum immunoglobulin ELISA, SPEP, flow cytometry and histological examination. We observed development of non-overlapping tumor types due to off-target Cre expression, but despite successful recombination in germinal center and later B-cell populations, we observed no B-cell phenotype. Together, these data demonstrate that Ras activation is not sufficient to transform primary germinal center B-cells, even in an Arf-null context, and that the temporal order of mutation acquisition may be critical for myeloma development. Specific pathways, yet to be identified, are required before Kras can contribute to the development of MM.
    PLoS ONE 06/2013; 8(6):e67941. DOI:10.1371/journal.pone.0067941 · 3.23 Impact Factor
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