CD40 and its ligand in the regulation of humoral immunity

doi:10.1006/smim.1994.1036

Seminars in Immunology

Volume 6, Issue 5, October 1994, Pages 279-286

https://doi.org/10.1006/smim.1994.1036 Get rights and content

Abstract

T cells provide help for B cell antibody production by cell-cell contact and by soluble factors. CD40L is the predominant protein induced on activated T cells which constitutes contact-dependent help, and lack of CD40L or blocking CD40-CD40L interactions leads to severely impaired antibody production. In addition to CD40-CD40L, B and T cells express costimulatory, accessory molecules which amplify T and B cell function and allow for reciprocal dialogues during antigen presentation. Interactions between costimulatory counter-receptors can determine lymphocyte activation or nonresponsiveness, and provides a means for regulating self-tolerance.

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Cited by (43)

Mechanisms underlying sCD40 production in hemodialysis patients
2012, Cellular Immunology
Citation Excerpt :
Its ligand, CD40L or CD154, is a 34–39 kDa type II integral membrane protein expressed on activated T cells, platelets and inflammatory cells [5–7]. The engagement of CD40 leads to B cell clonal expansion, germinal center formation, isotype switching, affinity maturation and generation of long-lived plasma cells [8,9]. Moreover, CD40/CD40L interaction is decisive in the regulation of antigen presenting cells (APC) and dendritic cells maturation and functions [10].
CD40 and its ligand (CD40L) regulate several cellular functions, including T and B-cell activation. The soluble form of CD40 (sCD40) antagonizes CD40/CD40L interaction. Patients undergoing hemodialysis (HD) present elevated sCD40 serum levels, which underlying molecular mechanisms are unknown.
We studied sCD40 serum and urinary levels, CD40 membrane and gene expression and membrane shedding in HD, uremic not-HD patients (UR) and healthy subjects (N).
We found that in HD sCD40 serum levels were higher than UR and N, being significantly elevated in anuric patients, and that sCD40 correlated to renal function in UR subjects, who presented also a reduced sCD40 urinary excretion rate. HD and UR presented reduced CD40 membrane and gene expression. The concentration of TNF-α converting enzyme (TACE), responsible for CD40 cleavage was not different between HD and N. Therefore the reduced renal clearance is the main cause of elevated sCD40 levels in HD. This finding could have relevant clinical implications.
Modulation of immune response to Toxoplasma gondii in sheep by immunization with a DNA vaccine encoding ROP1 antigen as a fusion protein with ovine CD154
2011, Veterinary Parasitology
Citation Excerpt :
After the booster injection, the IgG2/IgG1 ratios were at a median level suggesting a mixed Th1/Th2 response with high titers of IgG2 and IgG1 antigen-specific antibodies, respectively, with a predominant synthesis of IgG1 antibody isotype and a low or no production of IFN-γ. Previous studies have suggested that CD154 might enhance both humoral and cellular immune responses through: augmentation of total antibody production (including IgG1 and IgG2 subtypes), enhancing IL-12-dependent IFN-γ production and enhancing CTL activity (Gurunathan et al., 1998; Durie et al., 1994; Klaus et al., 1994; Noelle, 1998). Our studies have revealed that ROP1–CD154 fusion protein expressed during DNA immunization of sheep enhanced the IFN-γ and anti-ROP1 antibody levels.
CD154 is a cell surface molecule expressed by activated T cells. CD40 and CD154 interaction is critically important in regulating humoral and cell-mediated immune responses. In this study we have investigated whether a DNA vaccine encoding rhoptry protein 1 (ROP1) of Toxoplasma gondii, and encoding ovine CD154 induces an enhanced ROP1-specific immune response in sheep. Two groups of twelve animals received two intramuscular injections, of a DNA plasmid encoding T. gondii ROP1 antigen (group 1) or an ROP1 antigen fused to ovine CD154 (group 2). There were two control groups of sheep. One was injected with an empty vector (group 3) and the other received no injections at all (group 4).
The injection of the plasmid containing ROP1 (group 1) at weeks 0 and 4 induced a significant IgG2 response at week 2 which was amplified at week 4 after the booster injection and persisted to week 8 compared to the control animals in groups 3 and 4. For IgG1, significant differences from the control animals were only observed from week 5 onwards. The fusion of CD154 and ROP1 elicited significant IgG1 and IgG2 responses from week 1 which were amplified from weeks 5 to 8 compared to the control animals in groups 3 and 4. The IgG1 response was significantly higher in group 2 animals receiving pROP1-CD154 compared to group 1 receiving pROP1 only. There was no significant difference in IgG2 responses between groups 1 and 2. Significant differences in IFN-γ levels were only observed in treatment group 1 at week 2 and treatment group 2 at weeks 1 and 2 compared to the control animals.
The results demonstrated that an intramuscular injection of pROP1-CD154 gene to sheep significantly enhanced their immune response and induced a mixed Th1/Th2 response while the intramuscular injection of pROP1 only induced a Th1-specific immune response.
CD154-CD40-induced reactivation of latent HIV-1 infection
2003, Virology
Reservoirs of latent HIV-1 in T cells and macrophages pose one of the major obstacles that hamper final eradication of HIV-1 from infected patients. Targeting costimulatory molecules expressed on cell types harboring latent HIV-1 to achieve reactivation may provide a new approach to overcome this problem. One such molecule is CD40, a member of the tumor necrosis factor (TNF)-receptor family. Using THP89GFP cells as a model for latently infected macrophages, we demonstrate that trimeric forms of recombinant CD154 allow for the direct reactivation of latent HIV-1 infection. Reactivation is augmented by the release of TNF-α. The presence of TNF-α is also crucial for the expression of late structural genes such as p24 Gag. In addition, levels of secreted TNF-α are sufficiently high to reactivate latent HIV-1 in a latently HIV-1-infected T-cell line (J89GFP). Taken together, our results demonstrate that costimulatory molecules may be attractive targets to reactivate latent HIV-1 in infected patients.
CD45 is Required for CD40-induced Inhibition of DNA Synthesis and Regulation of c-Jun NH<inf>2</inf>-terminal Kinase and p38 in BAL-17 B Cells
2001, Journal of Biological Chemistry
Citation Excerpt :
To elucidate the mechanisms by which CD45 exerts its regulatory effects on CD40-induced inhibition of proliferation, we examined several signaling events mediated by CD40 ligation in BAL-17 and its CD45-deficient clone. As one of the activation events, CD40 ligation by anti-CD40 mAb was shown to up-regulate a number of cell surface molecules (24-29), and our findings suggest that CD45 is not involved in the CD40-induced up-regulation of CD54, CD80, CD86, CD95, and MHC class II (Table I). On the other hand, CD40-mediated activation of JNK and p38 was augmented and sustained in the CD45-deficient clone (Fig.4), and introduction of the CD45 gene resulted in recovery of the parental phenotype (Fig. 5).
Stimulation of B cell antigen receptor (BCR) may induce proliferation, differentiation, or apoptosis, depending upon the maturational stage of the cell and the presence or absence of signals transmitted via coreceptors. One such signal is delivered via CD40; for instance, ligation of CD40 rescues B cells from BCR-induced apoptosis. Here we show that, in contrast to WEHI-231 cells, CD40 ligation did not reverse BCR-induced growth inhibition in the BAL-17 mature B cell line and CD40 ligation itself inhibited proliferation. This inhibitory signaling was not observed in CD45-deficient cells. Further analyses demonstrate that transfection of dominant-negative form of SEK1 or treatment with SB203580 strongly reduced CD40-induced inhibition of BAL-17 proliferation, suggesting a requirement for c-Jun NH₂-terminal kinase and p38 in CD40-induced inhibition of proliferation. Interestingly, CD40-initiated activation of c-Jun NH₂-terminal kinase and p38 was enhanced and sustained in CD45-deficient cells, and these phenotypes were reversed by transfecting CD45 gene. However, CD40-mediated induction of cell surface molecules was not affected in CD45-deficient cells. Taken collectively, these results suggest that CD45 exerts a decisive effect on selective sets of CD40-mediated signaling pathways, dictating B cell fate.
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CD40 and its ligand in the regulation of humoral immunity