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PubMed1999

Expression of CD40 and its ligand, CD40L, in intestinal lesions of Crohn's disease.

OBJECTIVE: Selected mechanisms of the immune system participate in the development of inflammatory bowel disease. Recently, overexpression of the ligand for CD40 (CD40L), a lymphocyte costimulatory molecule, was shown to induce severe inflammatory bowel disease in transgenic mice. In the present study, we examined the expression of CD40 and CD40L on surgical specimens of ileum from 12 patients with Crohn's disease and 10 patients with diverticulitis. METHODS: Several CD40L+ cells were present in the affected tissue of patients with Crohn's disease, whereas few scattered CD40L+ cells were detected in sections of histologically normal ileum, resected distantly from the affected tissue, in patients with diverticulitis and in normal ileum portions obtained from colorectal cancer undergoing extensive surgery. The phenotype of CD40L+ cells was mainly CD4+. RESULTS: In patients with Crohn's disease, several CD40+ cells were detectable in the same areas of lymphocytes expressing CD40L, whereas in patients with diverticulitis, the number of CD40+ cells was significantly lower. Most of the CD40+ cells costained with CD20, thus showing to be B-lymphocytes, and only a few were CD14+ macrophages. Several von Willebrand-positive vessels were also positive for CD40. In addition, several infiltrating macrophages were found to express B7-1 and B7-2 molecules, the ligands of CD28 and CTLA-4, which cooperate with the CD40-CD40L pathway in lymphocyte activation. Staining of ileal lesions with anti-CTLA-4 antibodies resulted in detection of none or very few positive cells. In contrast, in patients with diverticulitis, an enhanced number of B7-1 and B7-2 and CTLA-4 was observed. CONCLUSION: The local accumulation of CD40L+ together with CD40+ cells within intestinal lesions of Crohn's disease suggests the involvement of this co-stimulatory pathway.

Abatacept↗
PubMed1996

Interleukin-12 production by dendritic cells. The role of CD40-CD40L interactions in Th1 T-cell responses.

Recent studies have demonstrated that the treatment of mice with anti-gp39 antibodies impairs T-cell functions in the murine collagen type II-induced arthritis model, in acute semi-allogenic graft-versus-host disease, and in the allo-specific CTL-reaction, that is, reactions that are believed to be mediated by Th1-type T cells. On the other hand, the administration of anti-gp39 antibody did not influence Th2 T-cells responses, suggesting that CD40-CD40L interactions are more crucial for Th1 than Th2 T-cell development. Recent studies also demonstrate that dendritic cells (DC) are capable of driving a Th1 T-cell response that is mediated by IL-12. In addition, stimulation of CD40 on human monocytes results in IL-12 production, suggesting that activated T cells expressing CD40L may directly induce the production of IL-12 by antigen-presenting cells, thus allowing for the generation of a Th1 T-cell response in the absence of intracellular pathogens. We investigated whether the CD40-CD40L interaction was important in the production of IL-12 by DCs in an in vitro system that allowed precise control of cytokine concentrations. Initially we showed that FACS-purified mouse spleen DCs produce high amounts of IL-12 p40 in response to CD40 crosslinking by CD40L-expressing fibroblasts. We then demonstrate that DCs also produce IL-12 p40 in a more physiologic system using purified DCs pulsed with ovalbumin (OVA) and then cultured with LECAM-1hi T cells from ovalbumin T-cell receptor transgenic mice. Finally, we show that IL-10 has a potent capacity to shut down CD40-induced IL-12 p40 secretion; and, in addition, IL-4 partially inhibits CD40-induced IL-12 p40 secretion and enhances IL-10-mediated inhibition in an additive fashion. We also investigated the in vivo relevance of this interaction in an experimental model for a Th1-mediated disease, the hapten reagent (TNBS)-induced colitis. The administration of anti-gp39 (CD40L) antibodies during the induction phase of the Th1 response completely prevented IFN-gamma production by CD4 T cells from the intestinal lamina propria and also the clinical and histological evidence of disease. In further studies we showed that the prevention of disease activity was due to an inhibition of IL-12 secretion. Thus, the injection of recombinant IL12 p75 heterodimer into TNBS + anti-gp39-treated mice reversed the effect of anti-gp39 and resulted in severe disease activity. In conclusion, these findings suggest that DCs produce IL-12 in response to CD40 signaling, that a mechanism by which IL-4 may induce Th2 development is by acting with IL-10 to inhibit IL-12 production by DCs, and that the CD40L-CD40 interaction is crucial for the IL-12-dependent priming of Th1 T cells in vivo.

Animals↗
PubMed2003

Functional CD40 expression induced following bacterial infection of mouse and human osteoblasts.

Bacterially induced bone infections often result in significant local inflammatory responses which are coupled with loss of bone. However, the mechanisms necessary for the protective host response, or those responsible for pathogen-induced bone loss, are not clear. Recent evidence demonstrates that bacterially infected osteoblasts secrete chemokines and cytokines, suggesting that these cells may have an unappreciated role in supporting localized inflammation. In this study, mouse and human osteoblasts were investigated for their ability to express functional CD40 upon exposure to two important pathogens of bone, Staphylococcus aureus and Salmonella enterica serovar Dublin. Bacterial infection of cultured mouse or human osteoblasts resulted in increased CD40 mRNA and CD40 protein expression induced by either pathogen. Importantly, CD40 expression by osteoblasts was functional, as assessed by ligation of this molecule with recombinant, soluble CD154. CD40 activity was assessed by induction of interleukin-6 and granulocyte-macrophage colony-stimulating factor in osteoblasts following ligation. Cocultures of activated CD4(+) T lymphocytes and osteoblasts could interact via CD40 and CD154, since an antibody against CD40 could block macrophage inflammatory protein-1alpha secretion. Taken together, these studies conclusively demonstrate that infected osteoblasts can upregulate expression of functional CD40 molecules which mediate cytokine secretion. This surprising result further supports the notion that bone-forming osteoblasts can directly interact with CD154-expressing cells (i.e., T lymphocytes) and can contribute to the host response during bone infection.

Animals↗
PubMed2001

Characterization of the CD154-positive and CD40-positive cellular subsets required for pathogenesis in retrovirus-induced murine immunodeficiency.

Genetically susceptible C57BL/6 (B6) mice that are infected with the LP-BM5 isolate of murine retroviruses develop profound splenomegaly, lymphadenopathy, hypergammaglobulinemia, terminal B-cell lymphomas, and an immunodeficiency state bearing many similarities to the pathologies seen in AIDS. Because of these similarities, this syndrome has been called murine AIDS (MAIDS). We have previously shown that CD154 (CD40 ligand)-CD40 molecular interactions are required both for the initiation and progression of MAIDS. Thus, in vivo anti-CD154 monoclonal antibody (MAb) treatment inhibited MAIDS symptoms in LP-BM5-infected wild-type mice when either a short course of anti-CD154 MAb treatment was started on the day of infection or a course was initiated 3 to 4 weeks after LP-BM5 administration, after disease was established. Here, we further characterize this required CD154-CD40 interaction by a series of adoptive transfer experiments designed to elucidate which cellular subsets must express CD154 or CD40 for LP-BM5 to induce MAIDS. Specifically with regard to CD154 expression, MAIDS-insusceptible B6 nude mice reconstituted with highly purified CD4+ T cells from wild-type, but not from CD154 knockout, B6 donors displayed clear MAIDS after LP-BM5 infection. In contrast, nude B6 recipients that received CD8+ T cells from wild-type B6 donors did not develop MAIDS after LP-BM5 infection. B6 CD40 knockout mice, which are also relatively resistant to LP-BM5-induced MAIDS, became susceptible to LP-BM5-induced disease after reconstitution with highly purified wild-type B cells but not after receiving purified wild-type dendritic cells (DC) or a combined CD40+ population composed of DC and macrophages obtained from B6 SCID mouse donors. Based on these and other experiments, we thus conclude that the cellular basis for the requirement for CD154-CD40 interactions for MAIDS induction and progression can be accounted for by CD154 expression on CD4+ T cells and CD40 expression on B cells.

Adoptive Transfer↗
PubMed1996

Activation of NF-kappaB/Rel by CD40 engagement induces the mouse germ line immunoglobulin Cgamma1 promoter.

Interaction between CD40 on B cells and CD40 ligand (CD40L) on T cells has been shown to mediate T-cell contact help for B-cell proliferation, differentiation, and immunoglobulin isotype switching. It has recently been shown that cross-linking CD40 on mouse B cells induces germ line gamma1 and epsilon transcripts and that interleukin-4 synergizes with CD40 signaling to further induce these germ line transcripts. Germ line transcripts have been shown to be required for class switch recombination. Here we show that signaling via CD40 increases expression of a transiently transfected luciferase reporter plasmid driven by the germ line Cgamma1 promoter in M12.4.1 B-lymphoma cells. By linker-scanning mutation analysis of the promoter, we have identified a CD40-responsive region (CD40RR) which is able to confer inducibility by CD40L to a minimal c-fos promoter. The CD40RR contains three binding sites for NF-kappaB/Rel proteins which are each required for maximal induction of CD40RR activity by CD40L. Binding of the NF-kappaB/Rel proteins p50, p65, c-Rel, and RelB to the CD40RR is induced by CD40 signaling in M12.4.1 cells and in splenic B cells. Cotransfection of expression plasmids for p50 and p65 or p50 and RelB, but not c-Rel, into M12.4.1 cells transactivates the CD40RR and the germ line gamma1 promoter. These data demonstrate that NF-kappaB Rel proteins activated by CD40 ligation play an important role in induction of the germ line Cgamma1 promoter.

Animals↗
PubMed1998

CD40 and CD154 in cell-mediated immunity.

CD40-CD154-mediated contact-dependent signals between B and T cells are required for the generation of thymus dependent (TD) humoral immune responses. CD40-CD154 interactions are however also important in many other cell systems. CD40 is expressed by a large variety of cell types other than B cells, and these include dendritic cells, follicular dendritic cells, monocytes, macrophages, mast cells, fibroblasts, and endothelial cells. CD40- and CD154-knockout mice and antibodies to CD40 and CD154 have helped to elucidate the role of the CD40-CD154 system in immune responses. Recently published studies indicate that CD40-CD154 interactions can influence T cell priming and T cell-mediated effector functions; they can also upregulate costimulatory molecules and activate macrophages, NK cells, and endothelia as well as participate in organ-specific autoimmune disease, graft rejection, and even atherosclerosis. This review focuses on the role of the CD40-CD154 system in the regulation of many newly discovered functions important in inflammation and cell-mediated immunity.

Animals↗
PubMed2005

The role of CD40 in CD40L- and antibody-mediated platelet activation.

Our initial finding that CD40- and CD40 ligand (CD40L)-deficient mice displayed prolonged tail bleeding and platelet function analyzer (PFA-100) closure times prompted us to further investigate the role of the CD40-CD40L dyad in primary hemostasis and platelet function. Recombinant human soluble CD40L (rhsCD40L), chemical cross-linking of which suggested a trimeric structure of the protein in solution, activated platelets in a CD40-dependent manner as evidenced by increased CD62P expression. CD40 monoclonal antibody (mAb) M3, which completely blocked rhsCD40L-induced platelet activation, also prolonged PFA-100 closure times of normal human blood. In contrast, CD40 mAb G28-5 showed less potential in blocking rhsCD40L-induced CD62P expression and did not affect PFA-100 closure times. However, when added to the platelets after rhsCD40L, G28-5 significantly enhanced the platelet response by causing clustering of, and signaling through, FcgammaRII. Similarly, higher order multimeric immune complexes formed at a 1/3 molar ratio of M90, a CD40L mAb, to rhsCD40L induced strong Fcgamma RII-mediated platelet activation when translocated to the platelet surface in a CD40-dependent manner, including the induction of morphological shape changes, fibrinogen binding, platelet aggregation, dense granule release, microparticle generation and monocyte-platelet-conjugate formation. The results suggest that CD40 may play a role in primary hemostasis and platelet biology by two independent mechanisms: First, by functioning as a primary signaling receptor for CD40L and, second, by serving as a docking molecule for CD40L immune complexes. The latter would also provide a potential mechanistic explanation for the unexpected high incidence of CD40L mAb-associated thrombotic events in recent human and animal studies.

Animals↗
PubMed2000

The role of CD40-CD154 interaction in antiviral T cell-independent IgG responses.

Polyomavirus (PyV) infection elicits protective T cell-independent (TI) IgG responses in T cell-deficient mice. The question addressed in this report is whether CD40 signaling plays a role in this TI antiviral IgG response. Because CD40 ligand (CD40L) can be expressed on numerous cell types in addition to activated T cells, it is possible that cells other than T cells provide CD40L to signal through CD40 on B cells and hence positively influence the antiviral TI IgG responses. In this study we show, by blocking CD40-CD40L interactions in vivo with anti-CD40L Ab treatment in TCR betaxdelta-/- mice and by using SCID mice reconstituted with CD40-/- B cells, that the lack of CD40 signaling in B cells results in a 50% decrease in TI IgG secreted in response to PyV. SCID mice reconstituted with CD40L-/- B cells also responded to PyV infection with diminished IgG secretion compared with that of SCID mice reconstituted with wild-type B cells. This finding suggests that B cells may provide the CD40L for CD40 signaling in the absence of T cell help during acute virus infection. Our studies demonstrate that, although about half of the TI IgG responses to PyV are independent of CD40-CD40L interactions, these interactions occur in T cell-deficient mice and enhance antiviral TI Ab responses.

Animals↗
PubMed2001

CD40 activates NF-kappa B and c-Jun N-terminal kinase and enhances chemokine secretion on activated human hepatic stellate cells.

Activated hepatic stellate cells (HSCs) are the main producers of extracellular matrix in the fibrotic liver and contribute to hepatic inflammation through the secretion of chemokines and the recruitment of leukocytes. This study assesses the function of CD40 on human HSCS: Activated human HSCs express CD40 in culture and in fibrotic liver, as determined by flow cytometry, RT-PCR, and immunohistochemistry. CD40 expression is strongly enhanced by IFN-gamma. Stimulation of CD40 with CD40 ligand (CD40L)-transfected baby hamster kidney cells induces NF-kappaB, as demonstrated by the activation of I-kappaB kinase (IKK), increased NF-kappaB DNA binding, and p65 nuclear translocation. CD40-activated IKK also phosphorylates a GST-p65 substrate at serine 536 in the transactivation domain 1. Concomitant with the activation of IKK, CD40L-transfected baby hamster kidney cell treatment strongly activates c-Jun N-terminal kinase. CD40 activation increases the secretion of IL-8 and monocyte chemoattractant protein-1 by HSCs 10- and 2-fold, respectively. Adenovirally delivered dominant negative (dn) IKK2 and TNFR-associated factor 2dn inhibit IKK-mediated GST-I-kappaB and GST-p65 phosphorylation, NF-kappaB binding, and IL-8 secretion, whereas IKK1dn and NF-kappaB-inducing kinase dominant negative do not have inhibitory effects. We conclude that the CD40-CD40L receptor-ligand pair is involved in a cross-talk between HSCs and immune effector cells that contributes to the perpetuation of HSC activation in liver fibrosis through TNFR-associated factor 2- and IKK2-dependent pathways.

Animals↗
PubMed2003

Blockade of CD40-mediated signaling is sufficient for inducing islet but not skin transplantation tolerance.

Treatment of mice with a single donor-specific transfusion (DST) plus a brief course of anti-CD154 mAb to block CD40-mediated signaling uniformly induces donor-specific transplantation tolerance. Survival of islet allografts in treated mice is permanent, but skin grafts eventually fail unless recipients are thymectomized. The nature of the cellular mechanisms involved and the basis for the difference in survival of islet vs skin allografts are not known. In this study, we used CD40 knockout mice to investigate the role of CD40-mediated signaling in each component of the tolerance induction protocol: the DST, the graft, and the host. When CD40-mediated signaling was eliminated in only the DST or the graft, islet allografts were rapidly rejected. However, when CD40 signaling was eliminated in the host, approximately 40% of the islet allografts survived. When CD40 signaling was eliminated in the DST, the graft, and the host, islet grafts survived long term (>84 days), whereas skin allografts were rapidly rejected ( approximately 13 days). We conclude that transplantation tolerance induction in mice treated with DST and anti-CD154 mAb requires blockade of CD40-mediated signaling in the DST, the graft, and the host. Blockade of CD40-mediated signaling is necessary and sufficient for inducing islet allograft tolerance and is necessary but not sufficient for long-term skin allograft survival. We speculate that a requirement for regulatory CD4(+) T cells in skin allograft recipients could account for this differential response to tolerance induction.

Animals↗
PubMed2003

Platelet-activating factor mediates CD40-dependent angiogenesis and endothelial-smooth muscle cell interaction.

The aim of the present study was to investigate whether stimulation of CD40 expressed by endothelial or smooth muscle cells triggers the synthesis of platelet-activating factor (PAF), an inflammatory mediator with angiogenic properties, and whether PAF contributes to CD40-induced neoangiogenesis. The results obtained indicate that the interaction of CD40 with soluble CD154 or with CD154 expressed on the membrane of leukocytes (CD154-transfected J558 cells) or of activated platelets, stimulated the synthesis of PAF by endothelial cells but not by smooth cells. The synthesis of PAF triggered by activated platelets was inhibited by a soluble CD40-murine Ig fusion protein that prevents the interaction between membrane CD40 and CD154. Studies with specific inhibitors and evaluation of protein phosphorylation indicated the involvement in PAF synthesis of two intracellular signaling pathways leading to cytosolic phospholipase A(2) activation: a phospholipase Cgamma-protein kinase C-Raf-p42/p44-mitogen-activated protein kinase (MAPK) and a MAPK kinase-3/6-dependent activation of p38 MAPK. PAF synthesized by endothelial cells after CD40 stimulation was instrumental in the in vitro migration and vessel-like organization of endothelial cells, and in the interaction between endothelial cells and smooth muscle cells, as inferred by the inhibitory effect of two different PAF receptor antagonists, WEB2170 and CV3988. In vivo, blockade of PAF receptors prevented the angiogenic effect triggered by CD40 stimulation in a murine model of s.c. Matrigel implantation. In conclusion, these observations indicate that PAF synthesis induced by stimulation of endothelial CD40 contributes to the formation and organization of new vessels. This may be relevant in the vascular remodeling associated with tumor and inflammatory neoangiogenesis.

Animals↗
PubMed2004

The development of functional CD8 T cell memory after Listeria monocytogenes infection is not dependent on CD40.

The immunologic requirements for generating long-lived protective CD8 T cell memory remain unclear. Memory CD8 populations generated in the absence of CD4 Th cells reportedly have functional defects, and at least a subset of CD8 T cells transiently express CD40 after activation, suggesting that direct CD4-CD8 T cell interactions through CD40 may influence the magnitude and functional quality of memory CD8 populations. To ascertain the role of CD40 in such direct T cell interactions, we investigated CD8 T cell responses in CD40-/- mice after infection with Listeria monocytogenes, an intracellular bacterium that induces APC activation and thus priming of CD8 T cells independently of CD4 Th cell help through CD40. In this study we show that memory CD8 T cells generated in CD40-deficient mice show in vivo cytotoxicity and cytokine production equivalent to CD8 memory T cells from wild-type mice. Upon secondary Listeria infection, CD40-/- memory CD8 T cells expand to greater numbers than seen in wild-type mice. These results indicate that CD40 ligation on CD8 T cells, although reportedly a part of CD8 T cell memory development in an H-Y-directed response, is not needed for the development of functional memory CD8 T cell populations after Listeria infection.

Animals↗
PubMed2005

Activation of CD40 in cervical carcinoma cells facilitates CTL responses and augments chemotherapy-induced apoptosis.

In this study, we describe the expression and function of CD40, a TNF receptor family member, in cervical carcinomas. CD40 was present at very low levels in normal cervical epithelium but was overexpressed in human papillomavirus-infected lesions and advanced squamous carcinomas of the cervix. The stimulation of CD40-positive cervical carcinoma cell lines with soluble CD40L (CD154) resulted in activation of the NF-kappaB and MAPK signaling pathways and up-regulation of cell surface markers and intracellular molecules associated with Ag processing and presentation. Concomitantly, the CD154-induced activation of CD40 in carcinoma cells was found to directly influence susceptibility to CTL-mediated killing. Thus, CD40 stimulation in cervical carcinoma cell lines expressing a TAP-dependent human papillomavirus 16 E6 Ag epitope resulted in their enhanced killing by specific CTLs. However, CD154 treatment of carcinoma cells expressing proteasome-dependent but TAP-independent Ags from the EBV-encoded BRLF1 and BMLF1 failed to increase tumor cell lysis by specific CTLs. Moreover, we demonstrate that chemotherapeutic agents that suppress protein synthesis and reverse the CD40-mediated dissociation of the translational repressor eukaryotic initiation factor 4E-binding protein from the initiation factor eukaryotic initiation factor 4E, such as 5-fluorouracil, etoposide, and quercetin, dramatically increase the susceptibility of cervical carcinoma cells to CD40L-induced apoptosis. Taken together, these observations demonstrate the functional expression of CD40 in epithelial tumors of the cervix and support the clinical exploitation of the CD40 pathway for the treatment of cervical cancer through its multiple effects on tumor cell growth, apoptosis, and immune recognition.

Antigen Presentation↗
PubMed2006

CD40 expression by microglial cells is required for their completion of a two-step activation process during central nervous system autoimmune inflammation.

Microglial cells are monocytic lineage cells that reside in the CNS and have the capacity to become activated during various pathological conditions. Although it was demonstrated that activation of microglial cells could be achieved in vitro by the engagement of CD40-CD40L interactions in combination with proinflammatory cytokines, the exact factors that mediate activation of microglial cells in vivo during CNS autoimmunity are ill-defined. To investigate the role of CD40 in microglial cell activation during experimental autoimmune encephalomyelitis (EAE), we used bone marrow chimera mice that allowed us to distinguish microglial cells from peripheral macrophages and render microglial cells deficient in CD40. We found that the first step of microglial cell activation was CD40-independent and occurred during EAE onset. The first step of activation consisted of microglial cell proliferation and up-regulation of the activation markers MHC class II, CD40, and CD86. At the peak of disease, microglial cells underwent a second step of activation, which was characterized by a further enhancement in activation marker expression along with a reduction in proliferation. The second step of microglial cell activation was CD40-dependent and the failure of CD40-deficient microglial cells to achieve a full level of activation during EAE was correlated with reduced expansion of encephalitogenic T cells and leukocyte infiltration in the CNS, and amelioration of clinical symptoms. Thus, our findings demonstrate that CD40 expression on microglial cells is necessary to complete their activation process during EAE, which is important for disease progression.

Animals↗
PubMed1996

Identification of distinct domains in CD40 involved in B7-1 induction or growth inhibition.

Binding of CD40 ligand to CD40 on a murine B lymphoma M12 induces B7-1 and inhibits cell growth. We have used M12 lymphomas transfected with wild-type and mutant human CD40 molecules to identify regions of the CD40 cytoplasmic tail involved in these signal transduction events. We find that threonine residues at positions 227 and 234 in the cytoplasmic domain play important role in B7-1 induction, but have lesser importance in CD40-mediated growth inhibition. In contrast, a deletion mutant with only six amino acids in the cytoplasmic tail retains some growth-inhibitory function, but has no detectable B7-1 induction capacity. We also find that cAMP synergizes with CD40 signaling to induce high level B7-1 induction, and that the synergistic signal through CD40 requires either T227 or T234, but not both. Thus, we provide evidence for at least two distinct signaling domains in the CD40 molecule.

Animals↗
PubMed1996

Expression of the co-stimulatory molecule CD40 on melanoma cells.

We have previously shown that one of the co-factors required for generation of T-cell responses, B7.1, is variably expressed on melanoma cells. In the present studies we have examined the expression of another important co-factor in T-cell responses, viz., CD40, and investigated regulation of its expression and possible function(s). PCR analysis revealed mRNA for CD40 in all 18 cell lines established from metastatic melanoma and the majority of those from 6 primary melanoma. CD40 protein was detectable in approximately 50% of the cell lines by flow cytometry and in sections from only 2 of 20 melanoma. Expression of CD40 protein was increased in 2 of 3 cell lines with constitutive CD40 expression by interferon-gamma but not by granulocyte/macrophage colony-stimulating factor, interleukin-2 or tumor necrosis factor-alpha. Interaction of monoclonal antibody with CD40 on melanoma cells resulted in an increase in their cell division but did not increase expression of the costimulatory factor B7. Our results suggest that CD40 expression on melanoma may have important effects on their biology. The influence of CD40 expression on T-cell responses to melanoma remains to be investigated.

Antibodies, Monoclonal↗
PubMed1998

The CD40 TRAF family member interacting motif carries the information to rescue WEHI 231 cells from anti-IGM-induced growth arrest.

Engagement of the antigen receptor on WEHI 231 murine B lymphoma cells leads to growth arrest and induction of apoptosis. Concomitant signaling through CD40 sustains proliferation and rescues the cells from apoptosis. At the molecular level, CD40 has been shown to activate nuclear factor kappaB (NF-kappaB) and stress-activated protein kinase (SAPK). The aim of our present study was to define the stretch of the CD40 cytoplasmic tail responsible for mediating these effects in WEHI 231 cells. Using recombinant retroviruses with the enhanced green fluorescent protein as selection marker we transduced WEHI 231 cells with chimeric molecules consisting of the extracellular and transmembrane region of human CD40 or rat CD4 and selected portions of the murine CD40 tail. Chimeric molecules with cytoplasmic fragments encompassing the "CD40 tumor necrosis factor-associated factor family member interacting motif" (TIM) were able to sustain growth and to uphold NF-kappaB activity as efficiently as the whole intracellular region of CD40. While the potential of the motif relative to the whole cytoplasmic tail was independent of the heterologous part of the chimeras it was strongly influenced by its distance to the membrane. Placing the 17-amino acid stretch of the motif too close to the membrane, i. e. only two or four amino acids apart, destroyed its capacity to mitigate the anti-IgM effect. Activation of SAPK through the chimeric molecules always correlated with their ability to activate NF-kappaB activity and to rescue the cells from apoptosis induced by antigen receptor ligation. Our data indicate that CD40-TIM carries most if not all of the information needed to deliver the signals responsible for sustaining growth in anti-IgM-stimulated WEHI 231 cells.

Animals↗
PubMed1999

CD40-deficient mice infected with the defective murine leukemia virus LP-BM5def do not develop murine AIDS but produce IgE and IgG1 in vivo.

CD40-deficient mice, when inoculated with the LP-BM5def murine retorvirus, become infected and show virus expression similar to wild-type mice. However, unlike the wild-type mice, CD40-deficient mice do not develop symptoms of immunodeficiency, lymphoproliferative disease and the typical histological changes in the lymphoid tissue. These results show that the CD40-CD40 ligand (CD40L) interaction in vivo is essential for anergy induction and the subsequent development of immunodeficiency and pathologic expansion of lymphocytes. Infected CD40-deficient mice and their littermates express a similar pattern of cytokine mRNA, which is not biased towards a Th2 phenotype. Nevertheless, hypergammaglobulinemia is induced in infected wild-type and CD40-deficient mice. Surprisingly, murine AIDS infection even induces IgE production in CD40-deficient mice in vivo. Our data demonstrate that antibody class switch to IgE and IgG1 can be induced by a retroviral infection in vivo even in the absence of CD40-CD40L interaction and an apparent switch to a Th2 cytokine production.

Animals↗