Abstract
Semaphorins are important molecules in embryonic development and multiple semaphorins have been identified as having key roles in immune regulation. To date, there is little known about Semaphorin 4C (Sema4C) in immune biology. We report for the first time that Sema4C is inducible in human and murine B-cells and may be important for normal B-cell development. Human tonsillar B-cells were studied following activation via anti-CD40 antibodies in the presence or absence of representative Th1, Th2, and regulatory cytokines. Murine B-cells from WT and Sema4C-/- mice were similarly stimulated. B-cell phenotyping in WT and Sema4C mutant mice was performed by flow cytometry and lymphoid architecture was studied by immunohistochemistry. Sema4C expression and synapse formation were analyzed by confocal microscopy. Gene array studies performed on human tonsillar B-cells stimulated to produce IgE revealed that Sema4C was among the top genes expressed at 24 h, and the only semaphorin to be increased under Th2 conditions. Validation studies demonstrated that human and murine B-cells expressed Sema4C under similar conditions. Sema4C-/- mice had impaired maturation of B-cell follicles in spleens and associated decreases in follicular and marginal zone B-cells as well as impaired IgG and IgA production. In keeping with a potential role in maturation of B-cells, Sema4C was expressed predominantly on CD27+ human B-cells. Within 72 h of B-cell activation, Sema4C was localized to one pole in a synapse-like structure, in association with F-actin, B-cell receptor, and Plexin-B2. Cell polarization was impaired in Sema4C-/- mice. We have identified a novel immune semaphorin induced in human and murine B-cells under Th2 conditions. Sema4C appears to be a marker for human memory B-cells. It may be important for B-cell polarization and for the formation of normal splenic follicles.
Highlights
Semaphorins have important roles in neural development and angiogenesis, and have recently emerged as key molecules in immune regulation [1]
Purified B-lymphocytes were isolated from five atopic and five non-atopic randomly chosen children undergoing tonsillectomy as part of a study on B-cell responses to corticosteroids following exposure to Th2 cytokines
Since the abnormalities in B-cells noted in Semaphorin 4C (Sema4C)−/− mice appeared to be secondary maturation sites such as peripheral lymphoid tissues rather than in primary maturation sites like bone marrow, we investigated if this impaired maturation was associated with abnormalities in lymphoid morphology
Summary
Semaphorins have important roles in neural development and angiogenesis, and have recently emerged as key molecules in immune regulation [1]. Our laboratory is interested in the role that B-cells play in autoregulating Th2-mediated inflammation: we were the first to determine that human B-cells produced the key Th2 cytokine IL-13 [5], and identified signaling pathways related to expression of the IL-13R on human B-cells [6]. In this context, we undertook to uncover novel molecules induced by activation of B-cells via Th2 cytokines, the initiating steps for class switching and production of IgE. We report for the first time that Sema4C is inducible in human and murine B-cells and may be important for normal B-cell development
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