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At least 649 records · Page 36Linked to original sources
PubMed1994

Effect of IL-2 on immunoglobulin production by anti-CD40-activated human B cells: synergistic effect with IL-10 and antagonistic effect with IL-4.

Activation of B cells by anti-CD40 provides an excellent model to investigate the direct effect of various cytokines on Ig production. Using this culture system, we examined the effect of IL-2 alone or in combination with other cytokines. IL-2 alone had only a moderate effect on Ig production by anti-CD40-activated B cells if compared with the effect of IL-10. However, IL-2 significantly augmented the synthesis of IgM, IgA, and IgG, including all IgG subclasses by anti-CD40-activated B cells cultured in the presence of IL-10. Both IgD- and IgD+ B cells showed an increase of IL-10-induced Ig production if IL-2 was added to the culture. The addition of IL-2 also increased immunoglobulin synthesis by anti-CD40/IL-10-activated B cells from patients with common variable immunodeficiency (CVI) and defective IL-2 production, suggesting that in a subgroup of CVI patients the IL-2 deficiency may contribute to the observed hypogammaglobulinemia. In contrast, the addition of IL-2 had a suppressive effect on IgE and IgG4 production by B cells cultured in the presence of anti-CD40 and IL-4. These data demonstrate that IL-2 plays an active role in the regulation of Ig production via CD40 by anti-CD40-activated B cells.

Adult↗
PubMedDate not supplied

T-cell activation induced by anti-CD3 x anti-B-cell lymphoma monoclonal antibody is enhanced by pretreatment of lymphoma cells with soluble CD40 ligand.

T cells play a key role in the control of abnormal B cell proliferation. Factors that play a role in inadequate T cell responses include absence of expression of costimulatory and adhesion molecules by the malignant B cells and lack of cytotoxic T cells specific for tumor-associated antigens. A number of approaches have been used to enhance T cell response against malignant B cells. Agents such as soluble CD40 ligand can enhance expression of costimulatory molecules by the malignant B cells and improve their ability to activate T cells. Anti-CD3-based bispecific antibodies can retarget T cells toward the tumor cells irrespective of T cell specificity. We used the V 38C13 murine lymphoma model to assess whether the combination of soluble CD40 ligand and anti-CD3-based bispecific antibody can enhance T cell activation induced by malignant B cells more effectively than either approach alone. Expression of CD80, CD86, and ICAM-1 on lymphoma cells was up-regulated by soluble CD40 ligand. Syngeneic T cells were activated more extensively by lymphoma cells when the lymphoma cells were pre-treated with soluble CD40 ligand. Bispecific-antibody induced T cell activation was more extensive when lymphoma cells pretreated with soluble CD40 ligand were present. The combination of soluble CD40 ligand plus bispecific antibody enhanced the median survival of mice compared to mice treated with bispecific antibody alone. We conclude that pretreatment of tumor cells with agents capable of inducing costimulatory molecule expression, such as soluble CD40 ligand can enhance the ability of malignant B cells to activate T cells. This effect is enhanced by the addition of bispecific antibody. The combination of enhanced expression of costimulatory molecules and retargeting of T cells by bispecific antibody may allow for a more effective T-cell-based immunotherapy.

Animals↗
PubMed1995

Role of protein tyrosine kinases and phosphatases in isotype switching: crosslinking CD45 to CD40 inhibits IgE isotype switching in human B cells.

Protein tyrosine kinases and protein tyrosine phosphatases play an important role in the transduction of signals via antigen receptors in T and B cells, and in CD40-dependent B-cell activation. To examine the role of tyrosine kinases and phosphatases in B-cell isotype switching, we examined the effects of the engagement of the transmembrane phosphatase CD45 on the synthesis of IgE induced by IL-4 and anti-CD40 monoclonal antibody (mAb). Crosslinking CD45 to CD40 using biotinylated mAbs and avidin strongly inhibited CD40-mediated IgE synthesis in IL-4-treated human B cells. CD40/CD45 crosslinking did not affect epsilon germline transcription in B cells stimulated with IL-4, but strongly inhibited induction of S mu/S epsilon switch recombination as detected by a nested primer polymerase chain reaction assay. The B-cell src-type tyrosine kinase lyn, which is activated following CD40 engagement, is a potential target for the effects of CD45 observed in our experiments, because CD45/CD40 crosslinking resulted in the inhibition of CD40-mediated lyn phosphorylation and activation. These results suggest an important role for protein tyrosine kinases and phosphatases in CD40-mediated induction of isotype switching to IgE.

Antigens, CD↗
PubMed2006

The CD40-induced protection against CD95-mediated apoptosis is associated with a rapid upregulation of anti-apoptotic c-FLIP.

CD95/Fas and CD40 receptors are important regulators of cell survival during germinal center reaction. In this study we used a human follicular lymphoma cell line, HF1A3, to study molecular mechanisms of CD95-mediated apoptosis and CD40-induced rescue from apoptosis. CD95 stimulation induced activation of caspase-8 and -3, collapse of mitochondrial membrane potential (DeltaPsim), release of cytochrome c and fragmentation of nuclear DNA. All these apoptotic events were abrogated, when cells were pretreated with CD40 antibodies before CD95 stimulation. CD40 induced a rapid up regulation of both short and long isoforms of c-FLIP, as these proteins were detectable 4h after receptor stimulation. The induction of c-FLIP as well as the anti-apoptotic function of CD40 was completely abolished when NF-kappaB activity was inhibited by a selective inhibitor PDTC. We conclude that the anti-apoptotic signaling of CD40 involves NF-kappaB-mediated induction of c-FLIP proteins which can interfere with caspase-8 activation. However, it remains to be seen whether c-FLIP proteins are the only one ones involved in CD40-mediated protection.

Apoptosis↗
PubMed2003

Statins (HMG-CoA reductase inhibitors) reduce CD40 expression in human vascular cells.

OBJECTIVE: HMG-CoA reductase inhibitors (statins) possess anti-inflammatory and immunomodulatory properties that are independent of their lipid-lowering action. As the CD40-CD40L signaling pathway is implicated in the modulation of inflammatory responses between vascular cells, involving adhesion molecules, pro-inflammatory cytokines, chemokines, we sought to investigate the potential role of statins in regulating the expression of CD40. METHODS AND RESULTS: Using Western blot, flow cytometry and immunohistochemistry analyses, we observed that four different statins reduced IFN-gamma-induced CD40 expression in human vascular cells (endothelial cells, smooth muscle cells, macrophages and fibroblasts). This effect was dose-dependent (from 5 microM to 80 nM) and reversed by addition of L-mevalonate. Activation of vascular cells by human recombinant CD40L, as measured by ELISA for IL-6, IL-8 and MCP-1, was strongly reduced when cells were treated with statins. Immunostaining of human carotid atherosclerotic lesions of patients subjected to statin treatment revealed less CD40 expression on a 'per vascular cell' basis compared to control patients. Although many pleiotropic effects of statins are mediated by nitric oxide synthase (NOS)- or peroxisome proliferator-activated receptor (PPAR)-dependent signaling pathways, we observed similar statin-induced reduction of CD40 expression using NOS inhibitors or different PPAR ligands. CONCLUSION: Statins decrease CD40 expression and CD40-related activation of vascular cells. These effects are partially reversed by the HMG-CoA reductase product L-mevalonate and are mediated by NOS- or PPAR-dependent pathways. Altogether, these findings provide mechanistic insight into the beneficial effects of statins on atherogenesis. They also provide a scientific rationale for the use of statins as immunomodulators after organ transplantation.

Animals↗
PubMed1998

CD40 signaling in vascular cells: a key role in atherosclerosis?

Atherosclerosis is one of the most prevalent fatal diseases in Western societies, and results from an intricate interplay between diverse factors such as lipid metabolism, blood coagulation elements, cytokines, hemodynamic stress, and behavioral risk factors. Atherosclerotic lesions are characterized by the infiltration of immune competent cells such as macrophages and T-lymphocytes, the proliferation of intimal cells of the arterial wall, the accumulation of lipids and the deposition of extracellular matrix components. For some years, endothelial cells, smooth muscle cells, and macrophages have been accorded crucial roles in the process of atherosclerosis. The mechanisms by which these cells contribute to atherosclerosis include augmented expression of adhesion molecules, as well as secretion of proinflammatory cytokines, matrix metalloproteinases, and tissue factor within human and experimental atheroma. Much evidence supports the role of tissue factor in inciting the thrombosis that causes most acute coronary syndromes. Macrophage content and expression of tissue factor correlate with rupture and instability of the atherosclerotic plaque. Matrix metalloproteinases can digest the plaque's extracellular matrix, and thus impair its stability. Plaque rupture exposes circulating blood components to the tissue factor-rich lipid-core, inciting thrombosis. Despite the increasing appreciation that atherogenesis involves participation of inflammatory pathways within cellular interactions, mediators of local communication between the major cell types within atherosclerotic plaques remain incompletely defined. By early appearance, activated T-cells may act as the orchestrator of atherogenesis. Both soluble and contact-dependent mediators from T-cells may be crucial in the development of this prevalent disease. Recent reports have helped explain some of these questions by pointing to a role of contact dependent interaction between CD40 and CD40 ligand (CD40L, renamed CD154) as a stimulus for atheroma-associated cells. We and others have recently showed that activated T-lymphocytes within the atherosclerotic vessel wall express the CD40 ligand surface molecule, known to play a major role in several immunological pathways. In addition to activated T-lymphocytes, functional CD40 and CD40L are coexpressed by human vascular endothelial cells, smooth muscle cells and human macrophages in vitro as well as in situ in human atherosclerotic lesions. Recent studies indicate that CD40L activates atheroma-associated cells by promoting the expression of molecules thought to be involved in atherosclerosis, such as adhesion molecules, cytokines, matrix metalloproteinases, and tissue factor. Thus, CD40 ligation on these vascular wall cells may promote mononuclear cell recruitment, participate in the weakening of the plaque and set the stage for thrombosis, mechanisms of crucial importance in the process of atherosclerosis. The involvement of the CD40 signaling pathway may play major roles during atherogenesis by regulating antigen-specific T-cell responses to yield activation instead of tolerance, and the presence of functional CD40L on non-leukocytic cells associated with atherosclerotic lesion indicates a novel T-cell-independent route of inflammatory activation, a now well recognized component of atherogenesis. These findings establish a possible crucial role for CD40-CD40L interactions in a prevalent human disease.

Animals↗
PubMed2001

CD40 ligation for immunotherapy of solid tumours.

Tumour vaccines provide an important focus of current cancer research and are often based on the premise that although T-cells do respond naturally to certain tumours, this is usually weak and therefore ineffective at controlling disease. An integral and necessary part of a T-cell immune response involves triggering of CD40 on antigen-presenting cells (APC) by its ligand, CD154, on responding T helper (Th) cells. Furthermore, cytotoxic responses to tumours may fail because the Th-cell response is inadequate and unable to provide CD40 stimulation of APC. Growing evidence shows that stimulating APC with soluble CD40L or an agonistic anti-CD40 mAb can, at least in part, replace the need for Th cells and generate APC that are capable of priming cytotoxic T lymphocytes (CTL). The aim of this study was to investigate whether a range of solid tumours (CD40(-)) could be treated with anti-CD40 mAb. It was found that this treatment was effective, and correlated with the intrinsic immunogenicity and aggressiveness of the tumours. The mAb could be delivered locally or at a distal site, but increased antigen load provided by irradiated tumour cells added little to the effectiveness of the treatment. T-cells were required since cytokine (interferon-gamma) and CTL activity were demonstrated following treatment and the therapeutic efficacy was lost in nude mice. In addition, depletion of CD8(+) cells abrogated protection whilst depletion of CD4(+) cells had no effect. This study demonstrates that solid CD40(-) tumours are sensitive to anti-CD40 mAb therapy and that the response bypasses the need for Th cells.

Animals↗
PubMed2002

B-cell activation and allosensitization after left ventricular assist device implantation is due to T-cell activation and CD40 ligand expression.

Left ventricular assist device (LVAD) implantation is frequently complicated by B-cell activation and allosensitization, posing a significant risk to successful transplant outcome. This study investigated whether B-cell hyperreactivity and alloantibody production in LVAD recipients involves T-cell dependent pathways. T-cell calcium flux and nuclear translocation of NFATc were used to determine states of T-cell activation. Flow cytometry was used to assess human T- and B-cell activation after culture with LVAD-derived biomaterial particles. Sera from LVAD recipients and controls were tested for the presence of anti-HLA antibodies, and for soluble CD40 ligand. LVAD-derived biomaterial induced rapid and sustained calcium flux into normal T cells, resulting in calcineurin-dependent nuclear translocation of NFATc. This resulted in increased T-cell expression of CD40 ligand and subsequent B-cell activation, which was reduced by inhibitors of T-cell activation (CsA or anti-CD25 mAb) or by anti-CD40 ligand mAb. LVAD recipients demonstrated higher frequencies of anti-HLA antibodies and serum levels of soluble CD40 ligand compared with heart failure controls. The results indicate that exposure of human mononuclear cells to LVAD-derived biomaterial leads to T-cell dependent B-cell activation via CD40--CD40 ligand interaction, and suggest that treatment with calcineurin inhibitors or monoclonal antibodies against either CD25 or CD40 ligand could be effective at preventing B-cell hyperreactivity and allosensitization after LVAD implantation.

B-Lymphocytes↗
PubMed2002

Systemic treatment with anti-CD40 antibody stimulates Langerhans cell migration from the skin.

Epidermal Langerhans cells (LCs) play a pivotal role in the initiation of cutaneous immune responses. The maturation of LCs and their migration from the skin to the T cell areas of draining lymph nodes are essential for the delivery and presentation of antigen to naïve T cells. CD40, which acts as a costimulatory molecule, is present on LCs and the basal layer of keratinocytes in the skin. We show here that systemic treatment of mice with anti-CD40 antibody stimulates the migration of LCs out of the epidermis with a 70% reduction in LC numbers after 7 days, although changes in LC morphology are detectable as early as day 3. LC numbers in the epidermis returned to 90% of normal by day 21. As well as morphological changes, LC showed up-regulated levels of Class II and ICAM-1, with only minimal changes in CD86 expression 3 days following anti-CD40 treatment. Despite increased levels of Class II and ICAM-1, epidermal LC isolated from anti-CD40 treated mice were poor stimulators of a unidirectional allogeneic mixed leucocyte reaction (MLR), as were epidermal LC isolated from control mice. These results indicate that CD40 stimulation is an effective signal for LC migration, distinct from maturation of immunostimulatory function in the epidermis, which is not altered. These observations may have important implications for the mechanism of action of agonistic anti-CD40 antibodies, which have been used as an adjuvant in models of infection and experimental tumours and the primary immunodeficiency Hyper IgM syndrome caused by deficiency of CD40 ligand.

Animals↗
PubMed1996

CD40 antibodies defining distinct epitopes display qualitative differences in their induction of B-cell differentiation.

IgE production can be obtained in vitro by stimulating B lymphocytes with CD40 antibodies and interleukin-4 (IL-4). This stimulation also results in homotypic aggregation and cell proliferation. We have shown previously that IgE synthesis may be dependent on additional signals provided by the close cellular contact. Thus inhibition of the aggregation by lymphocyte function-associated antigen-1 (LFA-1) antibodies leads to a decrease in IgE production. In the present study we show that the inhibitory effect of LFA-1 antibodies is critically dependent on the CD40 antibody used for stimulation. Thus, while previously using the monoclonal antibody (mAb) S2C6, IgE production induced by the CD40 antibody mAb89 was generally higher and could be enhanced more than fivefold in the presence of LFA-1 antibodies. Similarly, the addition of the CD23 mAb MHM6, which blocked aggregation to a similar degree as the LFA-1 antibodies, inhibited S2C6-induced IgE production but enhanced that induced by mAb89. In contrast to these opposing effects on IgE synthesis, proliferation induced by the two CD40 antibodies was affected similarly by the blocking antibodies. As the interaction between CD23 and CD21 has been suggested to involve recognition of carbohydrate structures on CD21 by the lectin-like domain on CD23, we also tested the effect of some different sugars on IgE synthesis and proliferation. Addition of fucose-1-phosphate to anti-CD40 and IL-4-stimulated B cells completely inhibited IgE synthesis and proliferation. Inhibition was also seen with mannose-6-phosphate but not with glucose-1-phosphate. In contrast to the MHM6 antibody, the effect of the sugars was similar irrespective of the CD40 antibody used for stimulation. The study shows that different antibodies to CD40 may give rise to qualitatively distinct signals depending on the epitope recognized.

B-Lymphocytes↗
PubMed1997

Cloning, expression and biological function of the bovine CD40 homologue: role in B-lymphocyte growth and differentiation in cattle.

Members of the tumour necrosis factor receptor superfamily play a key role in B-lymphocyte survival, proliferation, differentiation and programmed cell death. A member of this superfamily, the CD40 molecule plays an important role in the differentiation of B lymphocytes into effector cells and in early activation through cognate interaction with T lymphocytes. In this report, we describe a cDNA and its protein product identified in cattle with approximately 70% sequence conservation at the nucleic acid level with the human CD40 gene. Transcripts for the boCD40 molecule were identified in resting and activated B lymphocytes, some but not all CD4+ and CD8+ T lymphocyte clones, and peripheral blood-derived T lymphocytes. Coculture of resting B cells with simian virus 40 (SV40)-transformed NIH3T3 (MOP8) cells stably transfected with the ligand for CD40 (bovine CD40 ligand, boCD40L), resulted in proliferation which was enhanced by addition of rbo interleukin-4 (IL-4). Cross-linkage of CD40 on bovine B lymphocytes upon coculture with CD40L-transfected cells resulted in the increased production of secretory IgM and, to a lesser extent, of IgG. Addition of rboIL-4 to these cultures increased levels of IgM and IgG secretion approximately twofold over those induced by CD40L alone. Our results indicate that many of the functions described for human and mouse CD40 are also conserved in the bovine but that differences in subset distribution of expression of the CD40 molecule in lymphoid cell types in cattle may impact on regulation of the early activation steps in the acquired immune response.

Amino Acid Sequence↗
PubMed1998

Lymphotoxin-alpha is an important autocrine factor for CD40 + interleukin-4-mediated B-cell activation in normal and atopic donors.

Stimulation of human B cells with anti-CD40 + interleukin-4 (IL-4) results not only in proliferation and immunoglobulin E (IgE)-production, but also increased production of the cytokine lymphotoxin-alpha (LT-alpha) (formerly also known as tumour necrosis factor-beta (TNF-beta)). Here, we studied the role of LT-alpha (TNF-beta) in B cells following stimulation with anti-CD40 + IL-4 from normal versus atopic donors. Anti-CD40 + IL-4 stimulation of peripheral blood mononuclear cells (PBMC) from atopic donors resulted in enhanced production of soluble LT-alpha (TNF-beta) and increased membrane LT-alpha (TNF-beta) expression on the B cells compared with normal donors. Functional evaluation of LT-alpha (TNF-beta) in CD40 + IL-4-stimulated B cells shows that recombinant LT-alpha (TNF-beta) induces proliferation of B cells and enhances CD40 + IL-4-mediated B-cell proliferation and IgE synthesis in both normal and atopic donors in a dose-dependent manner. These findings were supported by semiquantitative analysis of epsilon-germline transcripts using reverse transcription-polymerase chain reaction (RT-PCR) showing increased epsilon-germline transcription in the presence of LT-alpha. Furthermore, addition of anti-LT-alpha (anti-TNF-beta) to CD40 + IL-4-stimulated B cells partially inhibited proliferation and IgE synthesis in a dose-dependent manner indicating a role of endogenous LT-alpha (TNF-beta) production by B cells during continued CD40 + IL-4 stimulation. These data suggest that LT-alpha (TNF-beta) plays a potentially significant role during B-cell proliferation and IgE synthesis. Moreover, LT-alpha (TNF-beta) production seems to be differentially regulated in B cells from normal and atopic donors.

Antibodies, Monoclonal↗
PubMed2003

A Salmonella typhi OmpC fusion protein expressing the CD154 Trp140-Ser149 amino acid strand binds CD40 and activates a lymphoma B-cell line.

CD154 is a type II glycoprotein member of the tumour necrosis factor (TNF) ligand family, which is expressed mainly on the surface of activated T lymphocytes. The interaction with its receptor CD40, plays a central role in the control of several functions of the immune system. Structural models based on the homology of CD154 with TNF and lymphotoxin indicate that binding to CD40 involves three regions surrounding amino acids K143, R203 and Q220, and that strands W140-S149 and S198-A210 are critical for such interactions. Also, it has been reported that two recombinant CD154 fragments, including amino acid residues Y45-L261 or E108-L261 are biologically active, whereas other polypeptides, including S149-L261, are not. Therefore, we decided to construct a fusion protein inserting the W140-S149 amino acid strand (WAEKGYYTMS) in an external loop of the outer membrane protein C (OmpC) from Salmonella enterica serovar Typhi and assess its ability to bind CD40 and activate B cells. The sodium dodecyl sulphate-polyacrylamide gel electrophoresis demonstrated that the chimeric OmpC-gp39 protein conserved its ability to form trimers. Binding to CD40 was established by three variants of enzyme-linked immunosorbent assay, a direct binding assay by coating plates with a recombinant CD40-Fc protein and through two competition assays between OmpC-gp39 and recombinant CD154 or soluble CD40-Fc. Flow cytometry analysis demonstrated that OmpC-gp39 increased the expression levels of major histocompatibility complex II, CD23, and CD80, in Raji human B-cell lymphoma similarly to an antibody against CD40. These results further support that the CD154/CD40 interaction is similar to the TNF/TNF receptor. This is the first report of a bacterial fusion protein containing a small amino acid strand form a ligand that is able to activate its cognate receptor.

Amino Acid Sequence↗
PubMed1998

Phenotypic convergence and divergence of surface immunoglobulin and CD40 signals.

Both anti-CD40 antibodies and anti-immunoglobulin (Ig) coupled to Sepharose induced proliferation of resting B cells and suppressed lipopolysaccharide (LPS)-induced B-cell differentiation to immunoglobulin secretion at comparable levels determined with the plaque-forming assay and Ig RNA steady state levels. Anti-CD40 antibodies also increased the proliferation of B cells stimulated by T helper cells in vitro while suppressing their differentiation to Ig secretion. Further, B cells preactivated by anti-Ig, anti-CD40 or a combination of the two mitogens could be restimulated by anti-CD40 but not by anti-Ig antibodies. Phenotypic divergence of Ig and CD40 signals regarding surface expression of activation markers was observed. Restimulation of anti-Ig- or anti-CD40-prestimulated cells with anti-Ig induced apoptosis whereas apoptosis could be inhibited when cells were recultivated with anti-CD40.

Animals↗
PubMed2001

Mutations of CD40 gene cause an autosomal recessive form of immunodeficiency with hyper IgM.

CD40 is a member of the tumor necrosis factor receptor superfamily, expressed on a wide range of cell types including B cells, macrophages, and dendritic cells. CD40 is the receptor for CD40 ligand (CD40L), a molecule predominantly expressed by activated CD4(+) T cells. CD40/CD40L interaction induces the formation of memory B lymphocytes and promotes Ig isotype switching, as demonstrated in mice knocked-out for either CD40L or CD40 gene, and in patients with X-linked hyper IgM syndrome, a disease caused by CD40L/TNFSF5 gene mutations. In the present study, we have identified three patients with an autosomal recessive form of hyper IgM who fail to express CD40 on the cell surface. Sequence analysis of CD40 genomic DNA showed that one patient carried a homozygous silent mutation at the fifth base pair position of exon 5, involving an exonic splicing enhancer and leading to exon skipping and premature termination; the other two patients showed a homozygous point mutation in exon 3, resulting in a cysteine to arginine substitution. These findings show that mutations of the CD40 gene cause an autosomal recessive form of hyper IgM, which is immunologically and clinically undistinguishable from the X-linked form.

CD40 Antigens↗
PubMed1992

A 39-kDa protein on activated helper T cells binds CD40 and transduces the signal for cognate activation of B cells.

CD40 is a B-cell surface molecule that has been shown to induce B-cell growth upon ligation with monoclonal antibodies. This report shows that triggering via CD40 is essential for the activation of resting B cells by helper T cells (Th). A soluble fusion protein of CD40 and human immunoglobulin, CD40-Ig, inhibited the induction of B-cell cycle entry, proliferation, and differentiation by activated Th1 and Th2. The ligand for CD40 was identified as a 39-kDa membrane protein that was selectively expressed on activated Th. A monoclonal antibody specific for the 39-kDa protein inhibited CD40-Ig binding and also inhibited the activation of B cells by Th. These data indicate that the 39-kDa membrane protein expressed on activated Th is a binding protein for CD40 and functions to transduce the signal for Th-dependent B-cell activation.

Animals↗
PubMed1995

Characterization of a 23-kDa protein associated with CD40.

CD40 is a 45-kDa glycoprotein member of the tumor necrosis factor receptor (TNFR) family expressed on B cells, thymic epithelial cells, dendritic cells, and some carcinoma cells. The unique capacity of CD40 to trigger immunoglobulin isotype switching is dependent on the activation of protein-tyrosine kinases, yet CD40 possesses no kinase domain and no known consensus sequences for binding to protein-tyrosine kinases. Recently, an intracellular protein (CD40bp/LAP-1/CRAF-1) which belongs to the family of TNFR-associated proteins was reported to associate with CD40. We describe a 23-kDa cell surface protein (p23) which is specifically associated with CD40 on B cells and on urinary bladder transitional carcinoma cells. Protein microsequencing revealed that p23 shows no homology to any known protein. A rabbit antibody raised against a peptide derived from p23 recognized a 23-kDa protein in CD40 immunoprecipitates. In contrast to CD40bp/LAP-1/CRAF-1, p23 was not associated with TNFR p80 (CD120b). These findings suggest that p23 is a novel member of the CD40 receptor complex.

B-Lymphocytes↗
PubMed1999

NF-kappaB-mediated up-regulation of Bcl-x and Bfl-1/A1 is required for CD40 survival signaling in B lymphocytes.

Activation of CD40 is essential for thymus-dependent humoral immune responses and rescuing B cells from apoptosis. Many of the effects of CD40 are believed to be achieved through altered gene expression. In addition to Bcl-x, a known CD40-regulated antiapoptotic molecule, we identified a related antiapoptotic molecule, A1/Bfl-1, as a CD40-inducible gene. Inhibition of the NF-kappaB pathway by overexpression of a dominant-active inhibitor of NF-kappaB abolished CD40-induced up-regulation of both the Bfl-1 and Bcl-x genes and also eliminated the ability of CD40 to rescue Fas-induced cell death. Within the upstream promoter region of Bcl-x, a potential NF-kappaB-binding sequence was found to support NF-kappaB-dependent transcriptional activation. Furthermore, expression of physiological levels of Bcl-x protected B cells from Fas-mediated apoptosis in the absence of NF-kappaB signaling. Thus, our results suggest that CD40-mediated cell survival proceeds through NF-kappaB-dependent up-regulation of Bcl-2 family members.

Apoptosis↗