GO:0035631 CD40 receptor complex: Components, Assembly and Research Methods
Research-grade guide for scientists and biopharma professionals
Key Takeaways
• GO:0035631 (CD40 receptor complex) is a cellular component defined as a protein complex that contains at least CD40, a cell surface receptor of the TNF receptor superfamily, plus other signaling molecules.
• The complex assembles in human B cells and is regulated by receptor oligomerization and ligand binding.
• CD40 signaling depends on the CD40-CD154 interaction, whose crystal structure reveals the molecular basis of receptor activation.
• Structural studies of CD40 with therapeutic antibodies dacetuzumab and bleselumab provide templates for complex-targeted drug design.
• CD40-TRAF6 signaling in T cells regulates trained immunity, linking the complex to innate immune memory.
• The CD40 receptor complex is a key node in cancer immunotherapy, including agonistic anti-CD40 antibodies in pancreatic ductal adenocarcinoma.
Description
The CD40 receptor complex (GO:0035631) is a cellular component defined by the presence of CD40, a cell surface receptor of the tumor necrosis factor receptor (TNFR) superfamily, together with additional signaling molecules. CD40 is expressed on antigen-presenting cells such as B cells and dendritic cells, where it receives signals from CD154 (CD40L) expressed on activated T cells. The assembly and regulation of this complex in human B cells were demonstrated by Kuhné et al., who showed that CD40 forms oligomeric complexes and that complex formation is modulated by ligand binding. Because the complex sits at the interface of adaptive and innate immunity, it is a central research subject in immunology, oncology, and vaccine biology. Understanding its composition, assembly, and downstream signaling is essential for interpreting how CD40-directed therapeutics work.
CD40 receptor complex At A Glance
| GO ID | GO:0035631 |
|---|---|
| GO term | CD40 receptor complex |
| Ontology | cellular_component |
| Synonym | None listed in QuickGO |
| Major function | Serves as a cell surface signaling platform containing CD40 and associated signaling molecules to initiate downstream immune signaling |
| Definition | A protein complex that contains at least CD40 (a cell surface receptor of the tumour necrosis factor receptor (TNFR) superfamily), and other signaling molecules |
| Related ligand | CD154 (CD40L) |
| Key structural feature | Oligomeric receptor complex on the cell surface |
| Therapeutic relevance | Target of agonistic antibodies such as dacetuzumab and bleselumab |
What Is GO:0035631?
According to the Gene Ontology, GO:0035631 (CD40 receptor complex) is a protein complex that contains at least CD40, a cell surface receptor belonging to the tumor necrosis factor receptor (TNFR) superfamily, and other signaling molecules. In other words, it is not merely the CD40 receptor alone but the assembled signaling platform that includes CD40 and associated proteins that together initiate downstream signaling.
Why Is CD40 receptor complex Important in Cell Biology?
The CD40 receptor complex is important because it is the physical and functional unit through which CD40 transduces signals from CD154 into immune cell activation, and its assembly state determines signaling output. Structural and mutational analyses of the CD40-CD154 interface have clarified how receptor activation occurs, providing a framework for designing antibodies and small molecules that modulate this complex. In cancer, agonistic anti-CD40 antibodies are being developed to enhance antitumor immunity, and their activity depends on the composition and signaling of the CD40 receptor complex. In innate immunity, CD40-TRAF6 signaling within T cells regulates trained immunity, showing that the complex also controls long-term functional reprogramming of immune cells. Thus, GO:0035631 is a focal point for immunology, oncology, and therapeutic development.
• Defines the molecular platform for CD40-mediated immune activation in B cells and antigen-presenting cells.
• Provides the structural basis for CD40-CD154 receptor activation, as revealed by crystallographic and mutational analysis.
• Serves as the target of therapeutic antibodies including dacetuzumab and bleselumab, whose crystal structures with CD40 have been solved.
• Links to trained immunity through T cell-induced CD40-TRAF6 signaling.
• Is relevant to cancer immunotherapy, including agonistic anti-CD40 plus anti-PDL1 approaches in pancreatic ductal adenocarcinoma.
• Contributes to germinal center and follicular dendritic cell biology, which are central to humoral immunity.
• Is implicated in tertiary lymphoid structure development and maintenance in cancer.
• Provides a model system for studying TNF receptor superfamily assembly and regulation.
• May inform autoimmune and inflammatory disease research, given the role of CD40 signaling in immune activation.
Structure and Composition of CD40 receptor complex
CD40 as the core receptor
In simple terms: CD40 is the main protein in this complex, sitting on the cell surface to receive signals.
CD40 is a cell surface receptor of the tumor necrosis factor receptor (TNFR) superfamily and is the essential component of GO:0035631. It is expressed on B cells and other antigen-presenting cells, where it binds CD154 (CD40L) presented by activated T cells. The receptor's extracellular domain engages ligand, while its intracellular domain recruits signaling molecules.
Oligomeric assembly in B cells
In simple terms: CD40 molecules group together on the cell surface to form a working signaling unit.
Kuhné et al. demonstrated that CD40 assembles into oligomeric complexes in human B cells and that this assembly is regulated, providing direct evidence for the CD40 receptor complex as a discrete cellular component. The oligomeric state is thought to be important for efficient signal transduction, and ligand binding can modulate complex formation.
CD40-CD154 interface and activation
In simple terms: The shape of CD40 bound to its partner CD154 shows how the receptor is switched on.
Crystallographic and mutational analysis of the CD40-CD154 complex revealed the molecular details of receptor activation, including key contact residues that mediate binding and oligomerization. These structural insights explain how ligand engagement triggers conformational changes that propagate signals inside the cell.
Therapeutic antibody complexes
In simple terms: Antibodies that target CD40 bind to it in specific ways, and their structures have been solved.
Crystal structures of human CD40 in complex with the monoclonal antibodies dacetuzumab and bleselumab have been determined, showing how these therapeutic agents engage the receptor. These structures provide templates for understanding how antibody binding affects CD40 receptor complex assembly and signaling.
Associated signaling molecules
In simple terms: Other proteins join CD40 to pass the signal onward inside the cell.
The GO definition specifies that the CD40 receptor complex contains CD40 and other signaling molecules. Downstream signaling involves TRAF adaptors, as evidenced by T cell-induced CD40-TRAF6 signaling that regulates trained immunity. The exact composition of associated molecules can vary by cell type and context, but the complex serves as the signaling platform.
Key Genes Involved in GO:0035631 CD40 receptor complex
The following genes and proteins are directly implicated in the composition, regulation, or function of the CD40 receptor complex (GO:0035631) based on the cited literature.
| Gene | Major Role | Research Relevance |
|---|---|---|
| CD40 | Core receptor of the complex; binds CD154 and initiates signaling | Central to complex assembly and activation studies |
| CD40LG (CD154) | Ligand that binds CD40 and triggers receptor activation | Structural and mutational studies of receptor activation |
| TRAF6 | Adaptor protein mediating CD40 signaling, including trained immunity | Links complex to innate immune memory |
| TRAF2 | Adaptor protein potentially associated with CD40 signaling | Studied in the context of CD40 complex assembly |
| TRAF3 | Adaptor protein potentially associated with CD40 signaling | Studied in the context of CD40 complex assembly |
| TRAF5 | Adaptor protein potentially associated with CD40 signaling | Studied in the context of CD40 complex assembly |
| CD40 (dacetuzumab epitope) | Region of CD40 bound by therapeutic antibody dacetuzumab | Structural basis for antibody-based targeting |
| CD40 (bleselumab epitope) | Region of CD40 bound by therapeutic antibody bleselumab | Structural basis for antibody-based targeting |
| CD8+ T cells (T-bet, Tox) | T-bet to Tox ratio influenced by anti-CD40 therapy | Relevant to immunotherapy response in pancreatic cancer |
| IL-15 complex | Enhances agonistic anti-CD40 + anti-PDL1 therapy | Combination immunotherapy research |
| Follicular dendritic cells | Cells that interact with CD40 signaling in germinal centers | Germinal center and humoral immunity studies |
| Dendritic cells | Control tertiary lymphoid structure development and maintenance | Cancer immunology and lymphoid tissue studies |
| B cells | Express CD40 and assemble the receptor complex | Model system for complex assembly |
| T cells | Express CD154 and can induce CD40-TRAF6 signaling | Trained immunity and T cell biology |
| Thyroid autoimmunity (context) | CD40 signaling may contribute to autoimmune processes | Autoimmune disease research |
How Is CD40 receptor complex Regulated?
The assembly and activity of the CD40 receptor complex are regulated at multiple levels. In human B cells, CD40 oligomerization is a regulated process that can be influenced by ligand binding. The CD40-CD154 interaction itself is a key regulatory step, as structural studies show that specific contact residues determine activation. Downstream, CD40-TRAF6 signaling in T cells regulates trained immunity, indicating that the complex's signaling output can be reprogrammed. Therapeutic antibodies such as dacetuzumab and bleselumab bind CD40 in defined orientations, which may modulate complex assembly and downstream signaling. Additionally, the tumor microenvironment and cytokines such as IL-15 can influence the efficacy of CD40-directed therapies, as shown in pancreatic ductal adenocarcinoma models.
CD40 receptor complex and Human Disease
| Gene | Disease / Biology | Potential Experimental Model |
|---|---|---|
| CD40 | Cancer immunotherapy target | Knockout or knock-in cell lines to test anti-CD40 antibody responses |
| TRAF6 | Trained immunity regulation | Point mutation of TRAF6 binding site in CD40 |
| CD40LG (CD154) | CD40-CD154 activation in immune disorders | Overexpression of CD154 in co-culture systems |
| CD40 (dacetuzumab epitope) | Antibody-based cancer therapy | Knock-in of human CD40 epitope into mouse models |
| Dendritic cells (CD40 signaling) | Tertiary lymphoid structure development in cancer | Conditional knockout in dendritic cells |
Cancer immunotherapy
The CD40 receptor complex is a target for cancer immunotherapy because agonistic anti-CD40 antibodies can enhance antitumor immune responses. In pancreatic ductal adenocarcinoma, IL-15 complex enhances the efficacy of agonistic anti-CD40 plus anti-PDL1 by correcting the T-bet to Tox ratio in CD8+ T cells infiltrating tumors. Dendritic cells, which express CD40, control tertiary lymphoid structure development and maintenance in cancer, further linking the complex to antitumor immunity.
Autoimmune and inflammatory conditions
CD40 signaling is implicated in autoimmune processes, including thyroid autoimmunity, where aberrant immune activation may involve CD40-dependent pathways. The CD40 receptor complex is therefore a potential target for modulating autoimmune responses, although direct evidence in thyroid autoimmunity requires further study.
Trained immunity and innate immune memory
T cell-induced CD40-TRAF6 signaling regulates trained immunity, a form of innate immune memory. This places the CD40 receptor complex in the context of long-term functional reprogramming of innate immune cells, with implications for vaccine design and host defense.
Germinal center and lymphoid tissue biology
Follicular dendritic cells and germinal centers are critical for humoral immunity, and CD40 signaling is a key component of these structures. Dendritic cells also control tertiary lymphoid structure development and maintenance in cancer, indicating that CD40 receptor complex function extends to lymphoid tissue organization.
From CD40 receptor complex-Related Genes to Experimental Models
| Research Question | Suitable Model |
|---|---|
| What is the role of CD40 in immune cell activation? | CD40 knockout cell lines (e.g., B cells) |
| How does CD40 oligomerization affect signaling? | Point mutations in CD40 extracellular domain |
| How do therapeutic antibodies bind CD40? | Knock-in of human CD40 epitopes for dacetuzumab/bleselumab |
| What is the role of CD40-TRAF6 signaling in trained immunity? | TRAF6 point mutation or knockout in T cells |
| Can CD40 signaling be targeted in pancreatic cancer? | Overexpression of CD40 in tumor models with anti-CD40 therapy |
| How does CD40 signaling affect germinal centers? | Conditional knockout in follicular dendritic cells |
How to Study the CD40 receptor complex Process
| Method | What It Measures | Typical Application |
|---|---|---|
| Crystallography | Three-dimensional structure of CD40-antibody or CD40-CD154 complexes | Structure-guided drug design |
| Mutational analysis | Effect of specific residues on complex formation and activation | Mapping functional interfaces |
| Biochemical oligomerization assays | Assembly state of CD40 receptor complex | Studying receptor regulation in B cells |
| Flow cytometry | Surface expression of CD40 and associated molecules | Immune cell phenotyping |
| Functional T cell assays | T-bet/Tox ratio and trained immunity | Immunotherapy response studies |
| Immunohistochemistry | Tertiary lymphoid structures and germinal centers | Tissue-level analysis of immune structures |
| Co-immunoprecipitation | Protein-protein interactions within the complex | Identifying associated signaling molecules |
| CRISPR screening | Genes required for CD40 complex function | Discovery of novel regulators |
Structural biology (crystallography and mutagenesis)
Crystallographic and mutational analysis of the CD40-CD154 complex has been used to define the molecular basis of receptor activation. Crystal structures of CD40 with therapeutic antibodies dacetuzumab and bleselumab provide high-resolution views of the complex. These methods are essential for understanding how the CD40 receptor complex assembles and how antibodies modulate it.
Biochemical assembly assays
The assembly and regulation of the CD40 receptor complex in human B cells were studied using biochemical approaches that detect oligomeric complexes. These methods can reveal changes in complex formation upon ligand binding or other stimuli.
Functional immune assays
T cell-induced CD40-TRAF6 signaling and trained immunity were investigated using functional immune assays. In cancer models, the effects of agonistic anti-CD40 plus anti-PDL1 were assessed by analyzing T-bet and Tox ratios in CD8+ T cells. These assays link complex function to immune cell behavior.
Imaging and tissue analysis
Dendritic cells control tertiary lymphoid structure development and maintenance in cancer, which can be studied by imaging and tissue analysis. Follicular dendritic cells and germinal centers are also analyzed by histological and imaging methods. These approaches reveal the spatial organization of CD40-expressing cells in tissues.
How CRISPR Can Be Used to Study GO:0035631 CD40 receptor complex
Knockout
CRISPR knockout of CD40 or its associated signaling molecules (e.g., TRAF6) can abolish CD40 receptor complex function, enabling researchers to test its role in immune activation and trained immunity. Knockout of CD40 in B cells or dendritic cells can reveal its contribution to germinal center formation and tertiary lymphoid structures.
Point Mutation
Point mutations in CD40 or CD154 can be introduced to disrupt specific interaction interfaces identified by crystallography, allowing functional mapping of the CD40-CD154 complex. Similarly, point mutations in TRAF6 binding sites can dissect CD40-TRAF6 signaling in trained immunity.
Knock-in
Knock-in of human CD40 epitopes recognized by dacetuzumab or bleselumab into model systems can facilitate testing of therapeutic antibodies in vivo. Knock-in of tagged CD40 can also enable tracking of complex assembly and trafficking.
Overexpression
Overexpression of CD40 or CD154 can amplify CD40 receptor complex signaling, providing a system to study downstream effects such as T cell activation and cytokine production. Overexpression models are useful for screening agonists and antagonists of the complex.
How EDITGENE Supports CD40 receptor complex Research
Researchers studying CD40 receptor complex-related genes often need to determine whether a candidate gene is causally involved in complex assembly, signaling, or disease. EDITGENE provides a comprehensive suite of CRISPR-based services to create precisely engineered cell models for such investigations.
Contact EDITGENE today to design your custom CRISPR model for CD40 receptor complex research.
Frequently Asked Questions About CD40 receptor complex
What is the CD40 receptor complex?
The CD40 receptor complex (GO:0035631) is a protein complex that contains at least CD40, a cell surface receptor of the TNF receptor superfamily, and other signaling molecules.
What genes are involved in the CD40 receptor complex?
Key genes include CD40, CD40LG (CD154), and TRAF adaptors such as TRAF6, which mediate signaling.
What is the function of GO:0035631?
It serves as a signaling platform for CD40-mediated immune activation, including B cell activation and trained immunity.
How is the CD40 receptor complex assembled?
CD40 oligomerizes in human B cells, and assembly is regulated by ligand binding and other factors.
What diseases are associated with the CD40 receptor complex?
It is linked to cancer immunotherapy, autoimmune conditions, and trained immunity.
What is the CD40-CD154 interaction?
CD154 (CD40L) binds CD40 to activate the receptor complex, as shown by crystallographic and mutational studies.
How can I study the CD40 receptor complex in the lab?
Methods include crystallography, biochemical assembly assays, functional immune assays, and CRISPR knockout models.
What are therapeutic antibodies targeting CD40?
Dacetuzumab and bleselumab are monoclonal antibodies whose crystal structures with CD40 have been solved.
Is CD40 receptor complex involved in trained immunity?
Yes, T cell-induced CD40-TRAF6 signaling regulates trained immunity.
What CRISPR models are available for CD40 research?
Knockout, point mutation, knock-in, and overexpression models can be generated to study CD40 receptor complex function.
Conclusion
The CD40 receptor complex (GO:0035631) is a critical signaling platform that contains CD40 and associated molecules, and it plays central roles in immune activation, trained immunity, and cancer immunotherapy. Structural and functional studies have elucidated its assembly and activation mechanisms, providing a foundation for therapeutic targeting. Continued research using CRISPR-engineered models will further clarify its roles in health and disease.
References
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- 3. Kuhné MR et al.. 1997. Assembly and regulation of the CD40 receptor complex in human B cells.. J Exp Med 186(2):337-42 PMID: 9221764
- 4. Asano R et al.. 2024. Crystal structures of human CD40 in complex with monoclonal antibodies dacetuzumab and bleselumab.. Biochem Biophys Res Commun 714:149969 PMID: 38657446
- 5. An HJ et al.. 2011. Crystallographic and mutational analysis of the CD40-CD154 complex and its implications for receptor activation.. J Biol Chem 286(13):11226-35 PMID: 21285457
- 6. Jacobs MME et al.. 2024. Trained immunity is regulated by T cell-induced CD40-TRAF6 signaling.. Cell Rep 43(9):114664 PMID: 39178113
- 7. Schmiechen ZC et al.. 2025. IL-15 Complex Enhances Agonistic Anti-CD40 + Anti-PDL1 by Correcting the T-bet to Tox Ratio in CD8+ T cells Infiltrating Pancreatic Ductal Adenocarcinoma.. Cancer Immunol Res 13(6):847-866 PMID: 40072469
- 8. Liu YJ et al.. 1996. Follicular dendritic cells and germinal centers.. Int Rev Cytol 166:139-79 PMID: 8881775
