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Constitutive expression of the B7h ligand for inducible costimulator on naive B cells is extinguished after activation by distinct B cell receptor and interleukin 4 receptor-mediated pathways and can be rescued by CD40 signaling.

Liang L, Porter EM, Sha WC - J. Exp. Med. (2002)

Bottom Line: Although signaling through both B cell receptor (BCR) and IL-4 receptor (R) converge on the extinction of B7h mRNA levels, BCR down-regulation occurs through Ca2+ mobilization, whereas IL-4R down-regulation occurs through a distinct Stat6-dependent pathway.During antigen-specific B cell activation, costimulation through CD40 signaling can reverse both BCR- and IL-4R-mediated B7h down-regulation.These data suggest that the CD40-CD40 ligand signaling pathway regulates B7h expression on activated B cells and may control whether antigen-activated B cells can express B7h and costimulate cognate antigen-activated T cells through ICOS.

View Article: PubMed Central - PubMed

Affiliation: Division of Immunology, Cancer Research Laboratory, Department of Molecular and Cell Biology, University of California, Berkeley, CA 94720, USA.

ABSTRACT
The recently described ligand-receptor pair, B7h-inducible costimulator (ICOS), is critical for germinal center formation and antibody responses. In contrast to the induced expression of the related costimulatory ligands B7.1 and B7.2, B7h is constitutively expressed on naive B cells and is surprisingly extinguished after antigen engagement and interleukin (IL)-4 cytokine signaling. Although signaling through both B cell receptor (BCR) and IL-4 receptor (R) converge on the extinction of B7h mRNA levels, BCR down-regulation occurs through Ca2+ mobilization, whereas IL-4R down-regulation occurs through a distinct Stat6-dependent pathway. During antigen-specific B cell activation, costimulation through CD40 signaling can reverse both BCR- and IL-4R-mediated B7h down-regulation. These data suggest that the CD40-CD40 ligand signaling pathway regulates B7h expression on activated B cells and may control whether antigen-activated B cells can express B7h and costimulate cognate antigen-activated T cells through ICOS.

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Related in: MedlinePlus

BCR-mediated B7h down-regulation occurs through Ca2+ signaling, whereas IL-4–mediated down-regulation occurs through a distinct Stat6-dependent signaling pathway. (A) B7h down-regulation induced by BCR signaling is Ca2+ dependent. Purified B cells were treated for 24h with PMA alone, ionomycin alone, or a combination of both and stained for B7h expression. (B) B7h down-regulation by BCR signaling is CsA sensitive. Purified B cells were activated with PMA and ionomycin, anti-IgM F(ab′)2, IL-4, or untreated either in the presence (solid lines) or absence (solid filled) of CsA. After 24 h of stimulation, cells were stained for B7h expression compared with control staining (shaded histogram). (C) IL-4–mediated B7h down-regulation is Stat-6 dependent. Purified B cells from Stat6−/− and wild-type control mice were either untreated or activated with IL-4, anti-IgM F(ab′)2 and IL-4, or PMA and ionomycin. Cells were stained for B7h expression after 24 h of culture.
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fig4: BCR-mediated B7h down-regulation occurs through Ca2+ signaling, whereas IL-4–mediated down-regulation occurs through a distinct Stat6-dependent signaling pathway. (A) B7h down-regulation induced by BCR signaling is Ca2+ dependent. Purified B cells were treated for 24h with PMA alone, ionomycin alone, or a combination of both and stained for B7h expression. (B) B7h down-regulation by BCR signaling is CsA sensitive. Purified B cells were activated with PMA and ionomycin, anti-IgM F(ab′)2, IL-4, or untreated either in the presence (solid lines) or absence (solid filled) of CsA. After 24 h of stimulation, cells were stained for B7h expression compared with control staining (shaded histogram). (C) IL-4–mediated B7h down-regulation is Stat-6 dependent. Purified B cells from Stat6−/− and wild-type control mice were either untreated or activated with IL-4, anti-IgM F(ab′)2 and IL-4, or PMA and ionomycin. Cells were stained for B7h expression after 24 h of culture.

Mentions: Next, we examined the proximal signaling pathways downstream of BCR engagement that lead to the extinction of B7h mRNA levels by activating naive B cells with the phorbol ester, PMA, and the Ca2+ ionophore, ionomycin (Fig. 4 A). Treatment with the combination of PMA and ionomycin was observed to down-regulate B7h surface expression, similar to the down-regulation observed with BCR signaling. In fact, ionomycin treatment alone was as effective as PMA and ionomycin, whereas treatment with PMA alone did not affect B7h surface expression. These data indicate that Ca2+ mobilization downstream of BCR signaling can mediate B7h down-regulation. Consistent with this observation, treatment with the inhibitor of calcineurin, CsA, blocked the down-regulation of B7h by both PMA and ionomycin treatment, and by anti-IgM antibodies (Fig. 4 B). In contrast, CsA treatment did not block IL-4–mediated B7h down-regulation. These data suggest that although Ca2+–dependent signaling is necessary for BCR-mediated down-regulation of B7h, IL-4–mediated down-regulation occurs through a different signaling mechanism that also converges on the extinction of B7h mRNA levels.


Constitutive expression of the B7h ligand for inducible costimulator on naive B cells is extinguished after activation by distinct B cell receptor and interleukin 4 receptor-mediated pathways and can be rescued by CD40 signaling.

Liang L, Porter EM, Sha WC - J. Exp. Med. (2002)

BCR-mediated B7h down-regulation occurs through Ca2+ signaling, whereas IL-4–mediated down-regulation occurs through a distinct Stat6-dependent signaling pathway. (A) B7h down-regulation induced by BCR signaling is Ca2+ dependent. Purified B cells were treated for 24h with PMA alone, ionomycin alone, or a combination of both and stained for B7h expression. (B) B7h down-regulation by BCR signaling is CsA sensitive. Purified B cells were activated with PMA and ionomycin, anti-IgM F(ab′)2, IL-4, or untreated either in the presence (solid lines) or absence (solid filled) of CsA. After 24 h of stimulation, cells were stained for B7h expression compared with control staining (shaded histogram). (C) IL-4–mediated B7h down-regulation is Stat-6 dependent. Purified B cells from Stat6−/− and wild-type control mice were either untreated or activated with IL-4, anti-IgM F(ab′)2 and IL-4, or PMA and ionomycin. Cells were stained for B7h expression after 24 h of culture.
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2194020&req=5

fig4: BCR-mediated B7h down-regulation occurs through Ca2+ signaling, whereas IL-4–mediated down-regulation occurs through a distinct Stat6-dependent signaling pathway. (A) B7h down-regulation induced by BCR signaling is Ca2+ dependent. Purified B cells were treated for 24h with PMA alone, ionomycin alone, or a combination of both and stained for B7h expression. (B) B7h down-regulation by BCR signaling is CsA sensitive. Purified B cells were activated with PMA and ionomycin, anti-IgM F(ab′)2, IL-4, or untreated either in the presence (solid lines) or absence (solid filled) of CsA. After 24 h of stimulation, cells were stained for B7h expression compared with control staining (shaded histogram). (C) IL-4–mediated B7h down-regulation is Stat-6 dependent. Purified B cells from Stat6−/− and wild-type control mice were either untreated or activated with IL-4, anti-IgM F(ab′)2 and IL-4, or PMA and ionomycin. Cells were stained for B7h expression after 24 h of culture.
Mentions: Next, we examined the proximal signaling pathways downstream of BCR engagement that lead to the extinction of B7h mRNA levels by activating naive B cells with the phorbol ester, PMA, and the Ca2+ ionophore, ionomycin (Fig. 4 A). Treatment with the combination of PMA and ionomycin was observed to down-regulate B7h surface expression, similar to the down-regulation observed with BCR signaling. In fact, ionomycin treatment alone was as effective as PMA and ionomycin, whereas treatment with PMA alone did not affect B7h surface expression. These data indicate that Ca2+ mobilization downstream of BCR signaling can mediate B7h down-regulation. Consistent with this observation, treatment with the inhibitor of calcineurin, CsA, blocked the down-regulation of B7h by both PMA and ionomycin treatment, and by anti-IgM antibodies (Fig. 4 B). In contrast, CsA treatment did not block IL-4–mediated B7h down-regulation. These data suggest that although Ca2+–dependent signaling is necessary for BCR-mediated down-regulation of B7h, IL-4–mediated down-regulation occurs through a different signaling mechanism that also converges on the extinction of B7h mRNA levels.

Bottom Line: Although signaling through both B cell receptor (BCR) and IL-4 receptor (R) converge on the extinction of B7h mRNA levels, BCR down-regulation occurs through Ca2+ mobilization, whereas IL-4R down-regulation occurs through a distinct Stat6-dependent pathway.During antigen-specific B cell activation, costimulation through CD40 signaling can reverse both BCR- and IL-4R-mediated B7h down-regulation.These data suggest that the CD40-CD40 ligand signaling pathway regulates B7h expression on activated B cells and may control whether antigen-activated B cells can express B7h and costimulate cognate antigen-activated T cells through ICOS.

View Article: PubMed Central - PubMed

Affiliation: Division of Immunology, Cancer Research Laboratory, Department of Molecular and Cell Biology, University of California, Berkeley, CA 94720, USA.

ABSTRACT
The recently described ligand-receptor pair, B7h-inducible costimulator (ICOS), is critical for germinal center formation and antibody responses. In contrast to the induced expression of the related costimulatory ligands B7.1 and B7.2, B7h is constitutively expressed on naive B cells and is surprisingly extinguished after antigen engagement and interleukin (IL)-4 cytokine signaling. Although signaling through both B cell receptor (BCR) and IL-4 receptor (R) converge on the extinction of B7h mRNA levels, BCR down-regulation occurs through Ca2+ mobilization, whereas IL-4R down-regulation occurs through a distinct Stat6-dependent pathway. During antigen-specific B cell activation, costimulation through CD40 signaling can reverse both BCR- and IL-4R-mediated B7h down-regulation. These data suggest that the CD40-CD40 ligand signaling pathway regulates B7h expression on activated B cells and may control whether antigen-activated B cells can express B7h and costimulate cognate antigen-activated T cells through ICOS.

Show MeSH
Related in: MedlinePlus