Biomedical subjects

Bhaskar Srivastava

Publications and source records attributed to Bhaskar Srivastava.

7 recordsLinked to original sources

PubMed2006

Notch activity synergizes with B-cell-receptor and CD40 signaling to enhance B-cell activation.

How diverse environmental cues are integrated to regulate B-cell activation and development remains poorly understood. Here we show that Notch activity synergizes with B-cell receptor (BCR) and/or CD40 signaling to enhance several aspects of B-cell activation and function. We find that costimulation of follicular B cells with the Notch ligand Delta-like-1 leads to significant increases in BCR- and CD40-mediated proliferation and enhances production of IgG1(+) cells in vitro and in vivo. We further find that coengagement of Notch and the BCR results in increased activation of the MAPK pathway, and MAPK and Notch inhibitors prevent B-cell activation events mediated by coengagement of Notch and the BCR. These data suggest that the BCR and CD40 signaling pathways collaborate with the Notch pathway to optimize B-cell activation.

Animals↗

PubMed2006

Generation of peripheral B cells occurs via two spatially and temporally distinct pathways.

We have identified a population of newly formed bone marrow (BM) B cells that shares multiple characteristics with late transitional B cells in the spleen. Both late splenic transitional B cells and cells within this uncharacterized BM population expressed the cell-surface phenotype AA4(+) CD23(+), yet the developmental kinetics and the renewal rate of AA4(+) CD23(+) BM B cells mirrored recently formed BM B cells. Further, unlike the least mature B cells in the BM and spleen, AA4(+) CD23(+) BM B cells expressed the homing receptor CD62L, were dependent on the antiapoptotic cytokine receptor BR3 and the tec family kinase Btk, and proliferated in response to IL-4 plus CD40 stimulation. Finally, frequencies of lambda light chain-positive B cells declined among AA4(+) CD23(+) B cells in both the BM and spleen, suggesting that V-gene selection events correlate with CD23 expression in both compartments. These observations indicate that the first step in B-cell maturation occurs in both the BM and the periphery and suggest that recently formed B cells exit the BM as a heterogeneous pool of immature and semimature B cells.

Agammaglobulinaemia Tyrosine Kinase↗

PubMed2006

Regulation of peripheral B cell maturation.

Although it is clear that the final phases of B cell maturation occur after newly formed B cells exit the bone marrow, the mechanisms underpinning the maturation, selection, and long-term survival of immature peripheral B cells remain poorly understood. Here, we review recent advances in our understanding of how B cell receptor (BCR)-mediated signaling events integrate with additional environmental cues to promote the selection and differentiation of immature B cells into functionally distinct subpopulations of mature B cells. We pay particular attention to the role of the Baff cytokine family and the Notch receptor-ligand family and their unique roles in promoting B cell survival and differentiation into follicular and marginal zone B cells.

Animals↗

PubMed2006

Development and selection of edited B cells in B6.56R mice.

Tolerance to dsDNA is broken in mice with a high-affinity anti-DNA H chain transgene, 56R, on the C57BL/6 background (B6.56R). B6.56R produce more anti-dsDNA Abs than BALBc.56R. To investigate how anti-DNA Abs are regulated on the B6 background, phenotypic and genetic studies were performed. B6.56R have reduced numbers of B cells and phenotypically altered B cell subsets, including relative increases in the proportions of IgM-negative bone marrow B cells, cells with a marginal zone phenotype, and cells with a transitional T3 phenotype. The peripheral B cell repertoire in B6.56R is restricted: most B cells express the 56R H chain and use a similar, limited subset of editor L chains. DNA binding is more common in B6.56R because the repertoire is shifted toward L chains that are more permissive for DNA binding. H chain editing is also observed and is increased in spontaneous as compared with LPS hybridomas. A subset of spontaneous hybridomas appears to lack H chain expression.

Animals↗

PubMed2005

Characterization of marginal zone B cell precursors.

Selection of recently formed B cells into the follicular or marginal zone (MZ) compartments is proposed to occur by way of proliferative intermediates expressing high levels of CD21/35 and CD23. However, we show that CD21/35(high) CD23(+) splenocytes are not enriched for proliferative cells, and do not contribute substantially to the generation of follicular B cells. Instead, ontogenic relationships, steady-state labeling kinetics, and adoptive transfer experiments suggest that CD21/35(high) CD23(+) splenocytes serve primarily as precursors for MZ B cells, although their developmental potential seems to be broader and is influenced by environmental cues that are associated with lymphopenia. Furthermore, CD21/35(high) CD23(+) splenocytes share several key functional characteristics with MZ B cells, including their capacity to trap T-independent antigen and a heightened proliferative response to LPS. These observations challenge previous models of peripheral B cell maturation, and suggest that MZ B cells develop by way of CD21/35(high) CD23(+) intermediates.

Animals↗

PubMed2005

Models for peripheral B cell development and homeostasis.

Immature B cells undergo key maturation and selection events after migrating to peripheral lymphoid organs. We will review recent advances in our understanding of the cell populations and molecular interactions underlying the differentiation of immature peripheral B cells into mature marginal zone (MZ) and follicular B cells, and discuss potential mechanisms by which numbers of MZ and follicular B cells are maintained. We will also discuss current controversies over the identity of precursor cells for MZ and follicular B cells, and propose a potentially unifying model for precursor-product relationships in peripheral B cell maturation.

Animals↗

PubMed2004

Alternative routes to maturity: branch points and pathways for generating follicular and marginal zone B cells.

Positive and negative selection of developing B cells is critical for generating a functional non-pathogenic B-cell repertoire. Newly formed B cells in the bone marrow or peripheral lymphoid system can be eliminated by one of several negative selection mechanisms or recruited through a poorly understood positive selection mechanism. In this review, we focus on the growing literature on the relevance of immature (transitional) peripheral B cells to the area of B-cell positive selection, with an emphasis on the notion that transitional B cells can be subdivided into several functionally distinct subpopulations. In this discussion, we consider the nature of these transitional B-cell subsets and their relevance to selection events that influence whether developing B cells eventually give rise to follicular versus marginal zone B cells. In addition, we attempt to initiate a resolution of current controversies surrounding transitional B-cell subsets and offer an alternative model of peripheral B-cell maturation and the follicular versus marginal zone decision.

Animals↗