Soluble CD40 ligand can replace the normal T cell-derived CD40 ligand signal to B cells in T cell-dependent activation.

Lane, Peter J. L.; Brocker, Thomas; Hubele, Sabine; Padovan, Elisabetta; Lanzavecchia, Antonio; McConnell, Fiona M.

doi:10.1084/jem.177.4.1209

Cited by 250 publications

(122 citation statements)

References 15 publications

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“…Anti-IgD stimulated an increase in the total number of viable cells in B cell cultures containing rCD40L in the presence and absence of IL-4, consistent with previous reports (17,18,39,50). By tracking cell division, we noted that anti-IgD-treated B cells had progressed through further divisions than controls, particularly at early time points.…”

Section: Discussionsupporting

confidence: 91%

“…For example, specific Ag can alter the migration pathway of a recirculating B cell by stimulating it to migrate to the edge of a T cell zone within secondary lymphoid organs (43)(44)(45)(46). In addition, sIg signals have been shown to stimulate B cells to increase surface expression levels of a number of activation molecules (15,16), and to promote B cell division and differentiation to Ig-secreting cells both during and following the provision of T cell-independent stimuli (47-49) or T cell-dependent B cell stimuli (17,18,39,50). These effects of Ag will clearly play an enhancing role in promoting Ab secretion by increasing the rate by which B cells are stimulated by T cells.…”

Section: Discussionmentioning

confidence: 99%

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Cross-Linking Surface Ig Delays CD40 Ligand- and IL-4-Induced B Cell Ig Class Switching and Reveals Evidence for Independent Regulation of B Cell Proliferation and Differentiation

Rush

Hasbold

Hodgkin

2002

The Journal of Immunology

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T cells stimulate B cells to divide and differentiate by providing activating signals in the form of inducible membrane-bound molecules and secreted cytokines. Provision of these signals in vitro reproduces many of the consequences of T-B collaboration in the absence of any form of Ag stimulation. Although clearly not obligatory, Ag signals appear to play an important regulatory role in numerous aspects of the B cell response. To examine directly the effect of an Ag signal, naive B cells were stimulated in the presence of rCD40 ligand, with or without IL-4 in the presence or absence of different anti-Ig mAbs. Anti-Ig mAbs exerted variable effects on the B cell division rate, from enhancement to no effect to inhibition. In contrast, all anti-Ig mAbs tested inhibited division-linked isotype switching to IgG1 and IgE. Thus, B cell Ag receptor ligands could modify the rates of B cell expansion and class switching independently. The ability of anti-Ig reagents to modify class switching suggests the B cell Ag receptor may play an important role in the selection of Ig isotypes during T cell-dependent humoral immune responses to Ags of different physical structure.

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Section: Discussionsupporting

confidence: 91%

Section: Discussionmentioning

confidence: 99%

Cross-Linking Surface Ig Delays CD40 Ligand- and IL-4-Induced B Cell Ig Class Switching and Reveals Evidence for Independent Regulation of B Cell Proliferation and Differentiation

Rush

Hasbold

Hodgkin

2002

The Journal of Immunology

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“…The IC10 rat anti-mouse CD40 Ab and the biotinylated Jo2 anti-mouse Fas Ab were kindly provided by Dr. M. Howard (DNAX, Palo Alto, CA) and Dr. S. Nagata (Osaka Bioscience Institute), respectively. Culture supernatants from a myeloma cell line producing soluble CD40 ligand CD8 fusion protein (CD40L) (44), generously provided by Dr. P. Lane (Basel Institute for Immunology), were used at a fourfold dilution that was optimal for inducing proliferation of splenic B cells. Recombinant interleukin-4 was purchased from R&D Systems (Minneapolis, MN).…”

Section: Methodsmentioning

confidence: 99%

Altered antigen receptor signaling and impaired Fas-mediated apoptosis of B cells in Lyn-deficient mice.

Wang

Koizumi

Watanabe

1996

The Journal of Experimental Medicine

145

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SUlTIITIaryMice deficient in the src-related protein tyrosine kinase, Lyn, exhibit splenomegaly and accumulate lymphoblast-like and plasma cells in spleen as they age, resulting in elevated levels of serum IgM (10-20-fold of control) and glomerulonephritis due to the presence of immune complexes containing auto-reactive antibodies. It remains unclear, however, how antibodyproducing cells are accumulated in the lymphoid tissues of Lyn -/-mice.To elucidate the role of Lyn in B cell function, we have studied the proliferative responses to various stimuli and Fasmediated apoptosis in B cells from young Lyn -/-mice which do not yet show apparent abnormality such as splenomegaly. Compared with control B cells, Lyn -/-B cells were hyper responsive to anti-lgM-induced proliferation and defective in FcyRIIB-mediated suppression orB cell antigen receptor (BCR) signaling, indicating that Lyn is involved in the negative regulation of BCR signaling. In addition, the BCR-mediated signal in Lyn -/-B ceils, unlike that in control B cells, failed to act in synergy with either CD40-or IL-4 receptor-triggered signal in inducing a strong proliferative response, suggesting that the BCR signaling pathway in Lyn -/-B cells is altered from that in control B cells. Furthermore, Lyn -/-B cells were found to be impaired in the induction of Fas expression after CD40 ligation and exhibited a reduced susceptibility to Fas-mediated apoptosis. Moreover, BCR cross-linking in Lyn -/-B ceils suppressed Fas expression induced by costimulation with CD40 ligand and IL-4. Collectively, these results suggest that the accumulation of lymphoblast-like and plasma cells in Lyn -/-mice may be caused, in part, by the accelerated activation of B cells in the absence of Lyn, as well as the impaired Fasmediated apoptosis after the activation.T he B cell antigen receptor (BCR) 1 consists of membrane immunoglobulin M (IgM) non-covalently associated with disulfideqinked heterodimers of Igor and Ig[~ subunits which couple mlg to several protein tyrosine kinases (PTKs) (1). Cross-linking of the BCR rapidly activates two classes of PTKs: the src family kinases (Lyn, Fyn, Blk, Hck, and Lck) (2-5) and the Syk kinase (6, 7), resulting in the phosphorylation of several proteins (8, 9), including PTKs themselves, Igor and Ig[3 (10), phospholipase C-y (11), phosphatidylinositol (PI)-3 kinase (12, 13), the protooncogene product Vav (14-16), Ras GTPase-activating protein (17), Shc (18), and HS1 (19).The src-related kinase, Lyn, is expressed preferentially in hematopoietic cells and in cells of neural tissues (20,21). Lyn is physically associated with the BCR in B cells and is rapidly phosphorylated upon receptor cross-linking (2-5).1Abbreviations used in this paper: BCR, B cell antigen receptor; CD40L, CD40 ligand; Fc"/IIRB, B cell receptor for IgG Fc region; lgM, membrane immunoglobulin M; NMS, normal mouse serum; Pl, propidium iodide; PTK, protein tyrosine kinase; SHP-1, hematopoitic cell phosphatase; smlg, cell surface IgM.Lyn interacts with and phosphorylates the Syk ki...

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“…Recombinant human IL-4 (Intergen, Purchase, NY) was added to BJAB cell cultures at 10 ng/ml. CD40L is a soluble CD40L-CD8␣ fusion protein secreted from transfected J558L mouse myeloma cells cultured in RPMI 1640 medium-10% FCS (29) and was added to splenic B cell cultures at a final concentration of 20%. Supernatant from nontransfected J558L cell cultures was used as a control.…”

Section: Recombinant Il-4 Cd40l and Lpsmentioning

confidence: 99%

Activation of the Mouse Ig Germline ε Promoter by IL-4 Is Dependent on AP-1 Transcription Factors

Shen

Stavnezer

2001

The Journal of Immunology

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Induction of germline (GL) ε transcripts, an essential step preceding Ig isotype switching to IgE, requires activation of transcription factors by IL-4 and a B cell activator, e.g., CD40 ligand or LPS. We demonstrate that AP-1 (Fos and Jun), induced transiently by CD40 ligand or LPS, binds a DNA element in the mouse GL ε promoter. AP-1 synergizes with Stat6 to activate both the intact GL ε promoter and a minimal heterologous promoter driven by the AP-1 and Stat6 sites of the mouse GL ε promoter. By contrast, C/EBPβ, which trans-activates the human GL ε promoter, inhibits IL-4 induction of the mouse promoter, probably by attenuating the synergistic interaction between AP-1 and Stat6. Furthermore, AP-1 does not trans-activate the human GL ε promoter. Thus, induction of GL ε transcripts in mice and humans may be regulated differently. In addition, although mouse GL ε transcripts have a half-life of ∼100 min, the RNA level continues to increase for up to 24 h, and the promoter appears to be active for at least 2 days after B cell activation. Altogether, these data suggest that induction of AP-1 activity, although transient, is required for activation of the mouse GL ε promoter by IL-4-induced Stat6.

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Soluble CD40 ligand can replace the normal T cell-derived CD40 ligand signal to B cells in T cell-dependent activation.

Cited by 250 publications

References 15 publications

Cross-Linking Surface Ig Delays CD40 Ligand- and IL-4-Induced B Cell Ig Class Switching and Reveals Evidence for Independent Regulation of B Cell Proliferation and Differentiation

Cross-Linking Surface Ig Delays CD40 Ligand- and IL-4-Induced B Cell Ig Class Switching and Reveals Evidence for Independent Regulation of B Cell Proliferation and Differentiation

Altered antigen receptor signaling and impaired Fas-mediated apoptosis of B cells in Lyn-deficient mice.

Activation of the Mouse Ig Germline ε Promoter by IL-4 Is Dependent on AP-1 Transcription Factors

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