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: 5.36). 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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    • "Klf2 expression is first detected in the B cell compartment following productive pre-B cell receptor signaling in small resting pre-B lymphocytes (Schuh et al., 2008). This transcription factor is preferentially expressed in quiescent B cells (Bhattacharya et al., 2007; Fruman et al., 2002; Glynne et al., 2000), and we found that several factors that induce B cell activation quickly downregulated Klf2 expression (Figure S1A). Although transcription varied between B cell lineages (e.g. "
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    ABSTRACT: Follicular (FO) and marginal zone (MZ) B cells are maintained in distinct locations within the spleen, but the genetic basis for this separation is still enigmatic. We now report that B cell sequestration requires lineage-specific regulation of migratory receptors by the transcription factor Klf2. Moreover, using gene-targeted mice we show that altered splenic B cell migration confers a significant in vivo gain-of-function phenotype to FO B cells, including the ability to quickly respond to MZ-associated antigens and pathogens in a T cell-dependent manner. This work demonstrates that in wild-type animals, naive FO B cells are actively removed from the MZ, thus restricting their capacity to respond to blood-borne pathogens.
    Immunity 08/2010; 33(2):254-65. DOI:10.1016/j.immuni.2010.07.016 · 19.75 Impact Factor
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    • "As the ability to generate genome-wide expression profiles became more broadly adopted, a large number of studies focused on key molecules and pathways involved in B and T cell responses. In general, most of these studies: (1) compared two or more closely related cell types such as Th1 versus Th2 cells (Hamalainen et al., 2001; Yang et al., 2005), phenotypically defined naive, effector, memory (Holmes et al., 2005; Kaech et al., 2002; Lee et al., 2004; Willinger et al., 2005), and exhausted versus functional effector and memory T cells (Wherry et al., Immunity 32, February 26, 2010 ª2010 Elsevier Inc. 153 Immunity Perspective 2007), or subpopulations of B cells (Bhattacharya et al., 2007; Ehrhardt et al., 2008; Klein et al., 2003; Vinuesa et al., 2002), (2) examined changes in gene expression in response to some stimuli such as antigen or cytokines (Feske et al., 2001; Hess et al., 2004; Liu et al., 2002), or (3) tracked longitudinal changes in lymphocyte populations during an immune response (Kaech et al., 2002). One common theme that emerged from many of these studies is that they focused on detailed analysis of individual genes identified through transcriptional profiling via differential expression and a fold-change cutoff. "
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    ABSTRACT: Understanding heterogeneity in adaptive immune responses is essential to dissect pathways of memory B and T cell differentiation and to define correlates of protective immunity. Traditionally, immunologists have deconvoluted this heterogeneity with flow cytometry--with combinations of markers to define signatures that represent specific lineages, differentiation states, and functions. Genome-scale technologies have become widely available and provide the ability to define expression signatures--sets of genes--that represent discrete biological properties of cell populations. Because genomic signatures can serve as surrogates of a phenotype, function, or cell state, they can integrate phenotypic information between experiments, cell types, and species. Here, we discuss how integration of well-defined expression signatures across experimental conditions together with functional analysis of their component genes could provide new opportunities to dissect the complexity of the adaptive immune response and map the immune response to vaccines and pathogens.
    Immunity 02/2010; 32(2):152-61. DOI:10.1016/j.immuni.2010.02.001 · 19.75 Impact Factor
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    ABSTRACT: The terminal differentiation of B cells into antibody-secreting plasma cells is tightly regulated by a complex network of transcription factors. Here we evaluated the role of the Ets factor Spi-B during terminal differentiation of human B cells. All mature tonsil and peripheral blood B-cell subsets expressed Spi-B, with the exception of plasma cells. Overexpression of Spi-B in CD19(+) B cells inhibited, similar to the known inhibitor BCL-6, the expression of plasma cell-associated surface markers and transcription factors as well as immunoglobulin production, ie, in vitro plasma cell differentiation. The arrest in B-cell differentiation enforced by Spi-B was independent of the transactivation domain, but dependent on the Ets-domain. By chromatin immunoprecipitation and assays using an inducible Spi-B construct BLIMP1 and XBP-1 were identified as direct target genes of Spi-B mediated repression. We propose a novel role for Spi-B in maintenance of germinal center and memory B cells by direct repression of major plasma cell factors and thereby plasma cell differentiation.
    Blood 07/2008; 112(5):1804-12. DOI:10.1182/blood-2008-01-136440 · 10.43 Impact Factor
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