GO:0160162 CD27 signaling pathway: Costimulation, Genes, Functions and Research Methods
Research-grade guide for scientists and biopharma professionals
Key Takeaways
• GO:0160162 (CD27 signaling pathway) describes the molecular cascade initiated when the receptor CD27 binds its physiological ligand CD70, culminating in regulation of downstream cellular processes such as transcription.
• CD27 is a TNF receptor superfamily (TNFRSF) member that provides costimulatory signals essential for T cell activation, memory differentiation, and effector function.
• The CD27-TRAF2-SHP-1 axis is a key signaling module that shapes naive T cell activation and promotes memory-associated gene regulatory networks.
• CD27-CD70 interactions are implicated in autoimmune disease pathogenesis and in cancer, where CD70 is often upregulated and represents a therapeutic target.
• Dysregulated CD27 signaling influences responses to immune checkpoint blockade, as shown by spatial transcriptomics of macrophage infiltration in non-small cell lung cancer.
• CRISPR-based models (knockout, point mutation, knock-in, overexpression) enable precise dissection of CD27 pathway components and their roles in immune regulation.
Description
The CD27 signaling pathway (GO:0160162) is a biological process defined as the series of molecular signals initiated by binding of the cell surface receptor CD27 to its physiological ligand CD70, and ending with regulation of a downstream cellular process, e.g. transcription. CD27 is a member of the TNF receptor superfamily and acts as a costimulatory receptor on T cells, while CD70 is its ligand, expressed on activated antigen-presenting cells and some tumor cells. This pathway is critical for bridging innate and adaptive immunity, influencing T cell activation, survival, memory formation, and effector differentiation. Researchers study GO:0160162 to understand how costimulation shapes immune responses in health and disease. The pathway has been linked to autoimmune conditions, where aberrant CD27-CD70 interactions drive pathogenic T cell activation, and to cancer, where CD70 upregulation contributes to immune evasion and resistance to therapies such as EGFR tyrosine kinase inhibitors. Moreover, the CD27-TRAF2-SHP-1 signaling axis has been shown to promote memory-associated gene regulatory networks during naive T cell activation, highlighting its role in transcriptional reprogramming. Given its central role in immune regulation, the CD27 signaling pathway is a focus for therapeutic targeting and for basic research into T cell biology. Understanding its molecular components and regulatory mechanisms is essential for developing interventions in autoimmunity, cancer, and transplantation.
CD27 signaling pathway At A Glance
| GO ID | GO:0160162 |
|---|---|
| GO term | CD27 signaling pathway |
| Ontology | biological_process |
| Synonym | None |
| Definition | The series of molecular signals initiated by the binding of the cell surface receptor CD27 to its physiological ligand CD70, and ending with the regulation of a downstream cellular process, e.g. transcription. |
| Major function | Costimulatory signaling in T cells and other immune cells, leading to activation, differentiation, and memory formation. |
| Key ligands | CD70 (TNFSF7) |
| Key receptors | CD27 (TNFRSF7) |
| Major signaling mediators | TRAF2, SHP-1, NF-kB, MAPK pathways |
What Is GO:0160162?
In our own words, GO:0160162 (CD27 signaling pathway) refers to the entire set of molecular events that occur after the cell surface receptor CD27 binds to its natural ligand CD70. This binding triggers intracellular signaling cascades that ultimately regulate downstream cellular processes, including changes in gene transcription. The pathway is a key component of costimulatory signaling in immune cells, particularly T cells, and involves adaptor proteins such as TRAF2 and phosphatases like SHP-1.
Why Is CD27 signaling pathway Important in Cell Biology?
The CD27 signaling pathway is important because it serves as a critical costimulatory axis that modulates T cell responses, influencing outcomes in infectious diseases, autoimmunity, and cancer immunotherapy. Its role in promoting memory-associated gene regulatory networks makes it a central node in long-term immunity. Furthermore, CD27-CD70 interactions are being explored as therapeutic targets, with CD70 upregulation linked to drug resistance in cancers such as EGFR-mutant lung cancer, and the pathway's involvement in autoimmune pathogenesis suggests potential for targeted interventions.
• Essential for T cell costimulation and activation, bridging innate and adaptive immunity.
• Drives memory T cell differentiation through transcriptional reprogramming.
• Implicated in autoimmune diseases such as rheumatoid arthritis and lupus.
• CD70 upregulation contributes to resistance to EGFR tyrosine kinase inhibitors in lung cancer.
• Modulates responses to anti-PD1/PD-L1 immunotherapy in non-small cell lung cancer.
• Potential target for cancer immunotherapy and vaccine adjuvants.
• Involved in graft-versus-host disease (GvHD) pathogenesis.
• Provides a model for studying TNF receptor superfamily signaling mechanisms.
• Enables research into mitochondrial ROS signaling during T cell activation.
• Offers opportunities for CRISPR-based functional genomics in immune cells.
What Happens During CD27 signaling pathway?
Ligand Binding and Receptor Activation
In simple terms: CD70 binds to CD27 on the cell surface, like a key fitting into a lock, to start the signaling process.
The CD27 signaling pathway is initiated when the trimeric ligand CD70 binds to CD27, a type I transmembrane receptor of the TNF receptor superfamily. This binding induces receptor trimerization and conformational changes that allow recruitment of intracellular adaptor proteins. CD27 is constitutively expressed on naive T cells and upregulated upon activation, while CD70 is transiently expressed on activated antigen-presenting cells, ensuring tight regulation of this interaction.
Recruitment of TRAF2 and Formation of the CD27-TRAF2-SHP-1 Axis
In simple terms: Inside the cell, CD27 recruits specific proteins like TRAF2 and SHP-1 to relay the signal.
Following ligand binding, the cytoplasmic tail of CD27 recruits TNF receptor-associated factor 2 (TRAF2), which serves as a scaffold for downstream signaling complexes. Recent studies have identified a CD27-TRAF2-SHP-1 axis where SHP-1 (PTPN6) is also recruited, modulating the strength and duration of signaling. This axis is critical for shaping naive T cell activation and promoting memory-associated gene regulatory networks.
Activation of Downstream Signaling Cascades
In simple terms: The signal then branches into multiple pathways that tell the cell to activate, survive, or proliferate.
TRAF2 recruitment leads to activation of NF-kB, MAPK (ERK, JNK, p38), and PI3K-Akt pathways. These cascades transmit signals to the nucleus, resulting in changes in gene expression that drive T cell activation, survival, and effector functions. The balance between activating and inhibitory signals is fine-tuned by phosphatases such as SHP-1, which can dampen the response.
Transcriptional Reprogramming and Memory Formation
In simple terms: The final step is changing which genes are turned on or off, helping T cells become long-lived memory cells.
Activation of transcription factors such as NF-kB and AP-1 leads to expression of genes involved in T cell memory, including those regulating metabolic fitness and survival. The CD27-TRAF2-SHP-1 axis specifically promotes memory-associated gene regulatory networks during naive T cell activation, as shown by transcriptomic analyses. This transcriptional reprogramming is essential for establishing long-term immunity.
Integration with Other Costimulatory and Checkpoint Signals
In simple terms: CD27 signaling works together with other signals to fine-tune the immune response.
CD27 costimulation integrates with signals from other TNF receptor superfamily members (e.g., CD28, 4-1BB, OX40) and checkpoint receptors (e.g., PD-1) to determine the overall T cell response. This integration ensures appropriate activation against pathogens while maintaining tolerance. Dysregulation of this balance can lead to autoimmunity or ineffective anti-tumor immunity.
Key Genes Involved in GO:0160162 CD27 signaling pathway
The following genes and proteins are central to the CD27 signaling pathway, based on published literature.
| Gene | Major Role | Research Relevance |
|---|---|---|
| CD27 | Receptor for CD70; initiates signaling | Target for costimulatory agonists in cancer immunotherapy |
| CD70 | Ligand for CD27; expressed on activated APCs and tumors | Therapeutic target in cancer; biomarker of EMT-associated resistance |
| TRAF2 | Adaptor protein recruited to CD27; activates NF-kB and MAPK | Key mediator of CD27 signaling; knockout models reveal pathway dependence |
| SHP-1 (PTPN6) | Phosphatase that modulates CD27 signaling strength | Regulates the CD27-TRAF2-SHP-1 axis; affects memory formation |
| NFKB1 | Transcription factor downstream of CD27 | Drives expression of survival and memory genes |
| MAPK1 (ERK2) | Kinase in MAPK cascade downstream of CD27 | Links CD27 to proliferation and effector functions |
| PIK3CA | Catalytic subunit of PI3K; activates Akt | Mediates survival signals from CD27 |
| AKT1 | Serine/threonine kinase; promotes survival and metabolism | Downstream of CD27 costimulation |
| TNFSF7 (CD70) | Gene encoding CD70 ligand | Upregulated in autoimmune diseases and cancers |
| TNFRSF7 (CD27) | Gene encoding CD27 receptor | Polymorphisms linked to autoimmune susceptibility |
| PTPN6 (SHP-1) | Gene encoding SHP-1 phosphatase | Modulates CD27 signaling; potential target for tuning immune responses |
| TRAF5 | Adaptor protein with redundant functions to TRAF2 | May compensate in TRAF2-deficient settings |
| BIRC2 (cIAP1) | E3 ubiquitin ligase recruited by TRAF2 | Regulates NF-kB activation downstream of CD27 |
| BIRC3 (cIAP2) | E3 ubiquitin ligase; partner of TRAF2 | Modulates CD27-induced NF-kB signaling |
| MAP3K7 (TAK1) | Kinase activated by TRAF2; activates NF-kB and MAPK | Central node in CD27 signaling |
| IKBKB (IKK-beta) | Kinase required for NF-kB activation | Essential for CD27-induced transcription |
| RELA (p65) | NF-kB subunit; transcription factor | Drives gene expression changes downstream of CD27 |
| JUN | AP-1 transcription factor component | Contributes to CD27-induced transcriptional reprogramming |
How Is CD27 signaling pathway Regulated?
The CD27 signaling pathway is tightly regulated at multiple levels. Receptor expression is controlled by T cell activation status, with CD27 constitutively present on naive T cells and downregulated upon terminal differentiation. Ligand availability is limited by transient CD70 expression on activated antigen-presenting cells. Intracellularly, the pathway is modulated by phosphatases such as SHP-1, which can dephosphorylate key signaling intermediates and dampen the response. Additionally, ubiquitination and degradation of TRAF2 and other adaptors by E3 ligases provide negative feedback. Cross-talk with other costimulatory and checkpoint pathways (e.g., PD-1) further shapes the outcome of CD27 signaling. Mitochondrial reactive oxygen species (ROS) signaling has also been shown to be required for antigen-specific T cell activation, potentially intersecting with CD27 costimulation.
CD27 signaling pathway and Human Disease
| Gene | Disease / Biology | Potential Experimental Model |
|---|---|---|
| CD70 | Autoimmune disease; cancer (NSCLC, EGFR TKI resistance) | CD70 knockout or overexpression in tumor cell lines; syngeneic mouse models |
| CD27 | Autoimmunity; immunodeficiency; cancer immunotherapy | CD27 knockout mice; human T cells with CRISPR knockout |
| TRAF2 | Inflammatory diseases; cancer | TRAF2 knockout cell lines; point mutations to disrupt CD27 binding |
| PTPN6 (SHP-1) | Autoimmunity; leukemia | SHP-1 knockout or phosphatase-dead knock-in models |
| NFKB1 | Inflammatory bowel disease; cancer | NFKB1 knockout organoids; CRISPR knock-in of risk variants |
CD27 Signaling in Autoimmune Disease
Dysregulated CD27-CD70 interactions contribute to the pathogenesis of autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus, and multiple sclerosis. Elevated CD70 expression on antigen-presenting cells can lead to excessive T cell costimulation, breaking tolerance and promoting tissue damage. Targeting this pathway is being explored as a therapeutic strategy in autoimmunity.
CD27 Signaling in Cancer and Immunotherapy
In cancer, CD70 is often overexpressed on tumor cells and can contribute to immune evasion by promoting T cell exhaustion or apoptosis. CD70 upregulation has been linked to resistance to EGFR tyrosine kinase inhibitors in non-small cell lung cancer, where it is associated with epithelial-mesenchymal transition (EMT). Conversely, CD27 agonists are being developed to boost anti-tumor T cell responses, and CD27 signaling influences sensitivity to anti-PD1/PD-L1 antibodies, as shown by spatial transcriptomics of macrophage infiltration in NSCLC.
CD27 Signaling in Graft-versus-Host Disease
CD27 costimulation plays a role in the pathogenesis of graft-versus-host disease (GvHD) following allogeneic hematopoietic stem cell transplantation. Interferons and other inflammatory signals can modulate CD27-CD70 interactions, influencing the balance between graft-versus-leukemia effects and GvHD. Targeting this pathway may help separate these outcomes.
CD27 Signaling in B Cell Biology
CD27 is also expressed on B cells, particularly memory B cells, and CD27 signaling contributes to B cell differentiation and antibody production. Single-cell multi-omic atlases of human B cell identity have revealed distinct CD27 expression patterns across B cell subsets, linking this pathway to humoral immunity.
From CD27 signaling pathway-Related Genes to Experimental Models
| Research Question | Suitable Model |
|---|---|
| Does CD27 signaling drive T cell memory formation? | CD27 knockout mice; adoptive transfer of CRISPR-edited T cells |
| What is the role of TRAF2 in CD27 signaling? | TRAF2 knockout Jurkat or primary T cells; point mutations in TRAF2 binding domain of CD27 |
| How does SHP-1 modulate CD27 signaling? | SHP-1 knockout or phosphatase-dead knock-in in T cell lines |
| Can CD70 overexpression induce T cell exhaustion? | CD70 overexpression in tumor cells; co-culture with T cells |
| What genes are regulated by CD27 costimulation? | RNA-seq and ATAC-seq after CD27 stimulation in wild-type vs. knockout T cells |
| Does CD27 signaling influence response to checkpoint blockade? | Humanized mouse models; spatial transcriptomics of NSCLC biopsies |
How to Study the CD27 signaling pathway Process
| Method | What It Measures | Typical Application |
|---|---|---|
| RNA-seq | Global gene expression changes | Identify transcriptional targets of CD27 signaling |
| scRNA-seq | Single-cell transcriptomes | Map CD27 expression across immune cell subsets |
| Phosphoproteomics | Phosphorylation events | Discover signaling nodes activated by CD27 |
| Flow cytometry | Surface markers and intracellular cytokines | Assess T cell activation and memory phenotype |
| Spatial transcriptomics | Gene expression in tissue context | Study CD27 signaling in tumor microenvironment |
| CRISPR knockout screens | Gene function at scale | Identify regulators of CD27-induced NF-kB |
| Immunoprecipitation-mass spectrometry | Protein-protein interactions | Map the CD27 signaling complex |
| Reporter assays | Pathway activity (e.g., NF-kB-luciferase) | Quantify CD27 signaling strength |
Transcriptomic Profiling (RNA-seq, scRNA-seq)
RNA sequencing and single-cell RNA sequencing are used to identify gene expression changes downstream of CD27 signaling. For example, comparing wild-type and CD27-knockout T cells after stimulation reveals memory-associated gene regulatory networks. Single-cell multi-omic atlases have also mapped CD27 expression across human B cell subsets.
Proteomic and Phosphoproteomic Analyses
Mass spectrometry-based proteomics can quantify protein interactions and phosphorylation events in the CD27 pathway. Immunoprecipitation of CD27 followed by mass spectrometry has identified TRAF2 and SHP-1 as key interactors. Phosphoproteomics can reveal signaling nodes activated downstream of CD27.
Flow Cytometry and Imaging
Flow cytometry is used to measure CD27 and CD70 surface expression, T cell activation markers, and cytokine production. Imaging techniques such as confocal microscopy can visualize CD27-CD70 interactions at the immunological synapse. Spatial transcriptomics has been applied to study macrophage infiltration and CD27 signaling in tumor tissues.
CRISPR Screens and Functional Genomics
Genome-wide CRISPR knockout screens can identify genes that modulate CD27 signaling. For example, screening for regulators of NF-kB activation downstream of CD27 can uncover novel pathway components. These screens are complemented by targeted knock-in of reporter genes to track pathway activity.
How CRISPR Can Be Used to Study GO:0160162 CD27 signaling pathway
Knockout
CRISPR knockout of CD27, CD70, TRAF2, or SHP-1 in T cell lines or primary T cells allows researchers to dissect their specific contributions to the pathway. For example, CD27 knockout abolishes costimulatory signals, while TRAF2 knockout impairs NF-kB activation. These models are essential for validating pathway components identified in screens.
Point Mutation
Point mutations can be introduced into CD27 to disrupt specific binding motifs, such as the TRAF2-binding site, without affecting overall receptor structure. This approach helps distinguish between signaling branches. Similarly, phosphatase-dead mutations in SHP-1 can reveal its role in modulating CD27 signaling.
Knock-in
Knock-in of tagged CD27 (e.g., HA or GFP) enables visualization and immunoprecipitation of the receptor complex. Knock-in of reporter genes under the control of CD27-responsive promoters (e.g., NF-kB) allows real-time monitoring of pathway activity. These models are valuable for drug discovery and functional studies.
Overexpression
Overexpression of CD70 in tumor cells or antigen-presenting cells can mimic pathological conditions where the ligand is upregulated, such as in autoimmune disease or cancer. Overexpression of constitutively active CD27 mutants can also be used to study downstream effects independent of ligand binding.
How EDITGENE Supports CD27 signaling pathway Research
Researchers studying CD27 signaling pathway-related genes often need to determine whether a candidate gene is causally involved in immune regulation, whether a specific mutation alters pathway activity, or whether overexpression mimics a disease state. EDITGENE provides a comprehensive suite of CRISPR-based services to address these questions with precision and reproducibility.
Contact EDITGENE today to design your custom CRISPR model for CD27 signaling pathway research.
Frequently Asked Questions About CD27 signaling pathway
What is the CD27 signaling pathway?
The CD27 signaling pathway (GO:0160162) is the series of molecular signals initiated by binding of the receptor CD27 to its ligand CD70, leading to regulation of downstream cellular processes such as transcription.
What genes are involved in CD27 signaling?
Key genes include CD27 (receptor), CD70 (ligand), TRAF2, SHP-1 (PTPN6), NFKB1, and MAPK1, among others.
What is the role of CD27 in T cell activation?
CD27 provides costimulatory signals that enhance T cell activation, survival, and memory formation, acting through TRAF2 and NF-kB pathways.
How is CD27 signaling linked to autoimmune disease?
Aberrant CD27-CD70 interactions can drive excessive T cell activation and break tolerance, contributing to autoimmune conditions like rheumatoid arthritis and lupus.
Is CD27 a target for cancer immunotherapy?
Yes, CD27 agonists are being developed to boost anti-tumor immunity, and CD70 upregulation is associated with resistance to EGFR inhibitors in lung cancer.
What is the CD27-TRAF2-SHP-1 axis?
It is a signaling module where CD27 recruits TRAF2 and SHP-1 to modulate downstream NF-kB and MAPK activation, influencing memory gene networks.
How can CRISPR be used to study CD27 signaling?
CRISPR knockout, point mutation, knock-in, and overexpression models allow precise dissection of CD27 pathway components in immune cells.
What diseases are associated with CD27 signaling?
Autoimmune diseases, cancers (e.g., NSCLC), and graft-versus-host disease have been linked to CD27-CD70 dysregulation.
What methods are used to study CD27 signaling?
Common methods include RNA-seq, phosphoproteomics, flow cytometry, spatial transcriptomics, and CRISPR screens.
Where can I get CRISPR models for CD27 pathway research?
EDITGENE provides custom knockout, point mutation, knock-in, overexpression, and library screening services for CD27 signaling genes.
Conclusion
The CD27 signaling pathway (GO:0160162) is a central costimulatory axis in immune regulation, with critical roles in T cell memory, autoimmunity, and cancer. Understanding its molecular components and regulatory mechanisms offers opportunities for therapeutic intervention. CRISPR-based models are indispensable for dissecting this pathway and translating findings into clinical applications.
References
- 1. Jaeger-Ruckstuhl CA et al.. 2024. Signaling via a CD27-TRAF2-SHP-1 axis during naive T cell activation promotes memory-associated gene regulatory networks.. Immunity 57(2):287-302.e12 PMID: 38354704
- 2. Watts TH et al.. 2025. TNF/TNFR Superfamily Members in Costimulation of T Cell Responses-Revisited.. Annu Rev Immunol 43(1):113-142 PMID: 39745933
- 3. Glass DR et al.. 2020. An Integrated Multi-omic Single-Cell Atlas of Human B Cell Identity.. Immunity 53(1):217-232.e5 PMID: 32668225
- 4. Nilsson MB et al.. 2023. CD70 is a therapeutic target upregulated in EMT-associated EGFR tyrosine kinase inhibitor resistance.. Cancer Cell 41(2):340-355.e6 PMID: 36787696
- 5. Kim B et al.. 2022. Editorial: Interferons and GvHD.. Front Immunol 13:853567 PMID: 35185939
- 6. Larroquette M et al.. 2022. Spatial transcriptomics of macrophage infiltration in non-small cell lung cancer reveals determinants of sensitivity and resistance to anti-PD1/PD-L1 antibodies.. J Immunother Cancer 10(5) PMID: 35618288
- 7. Han BK et al.. 2016. The CD27-CD70 pathway and pathogenesis of autoimmune disease.. Semin Arthritis Rheum 45(4):496-501 PMID: 26359318
- 8. Sena LA et al.. 2013. Mitochondria are required for antigen-specific T cell activation through reactive oxygen species signaling.. Immunity 38(2):225-36 PMID: 23415911
