GO:0002757 immune response-activating signaling pathway: Mechanism, Genes, Functions and Research Methods
Research-grade guide for scientists and biopharma professionals
Key Takeaways
• GO:0002757 (immune response-activating signaling pathway) describes the molecular signal transduction cascade triggered when a ligand binds its receptor, leading to activation or perpetuation of an immune response [1, 5].
• Key receptor-proximal hubs include NF-kB/p65, inflammasome sensors, and interferon-stimulated gene networks that convert ligand binding into transcriptional immune programs [6, 7].
• Dysregulation of this pathway is linked to severe COVID-19, autoimmune sclerosis, testicular cancer immune microenvironment, and impaired antiviral defense [2, 6, 7, 8].
• Single-cell and transcriptomic profiling are central methods for mapping pathway activity in patient tumors and blood, as shown in esophageal squamous cell carcinoma and influenza susceptibility studies [1, 5].
• CRISPR knockout, point-mutation, knock-in, and overexpression models allow causal testing of individual nodes within this pathway [4, 7].
• The pathway is highly context-dependent: the same NF-kB and inflammasome modules can drive protective immunity or pathological inflammation depending on tissue and timing [4, 6, 7].
Description
GO:0002757, immune response-activating signaling pathway, is a biological process defined as the series of molecular signals generated by a ligand binding to its receptor that lead to the activation or perpetuation of an immune response. In practical terms, this term captures the receptor-proximal and downstream signaling events that convert an extracellular or intracellular immune stimulus into a coordinated cellular response, including cytokine production, inflammasome activation, and antiviral gene expression [1, 5, 6]. The pathway is not a single linear cascade but a network of interconnected modules, and its output depends on cell type, ligand identity, and the presence of co-receptors or adaptors. For researchers, GO:0002757 matters because it provides a controlled vocabulary to annotate and compare immune signaling states across experiments. Transcriptomic studies of seasonal influenza A/H3N2 susceptibility have used baseline blood expression of immune signaling genes to identify individuals at risk, directly linking pathway activity to host outcome. Similarly, single-cell profiling of esophageal squamous cell carcinoma after neoadjuvant chemo-immunotherapy reveals dynamic changes in immune response-activating signaling that correlate with treatment response. In severe COVID-19, inflammasome-related genes within this pathway distinguish patient subgroups and predict disease severity. Mechanistically, the pathway often converges on NF-kB transcription factors, which are required for antiviral responses in vivo, as demonstrated in zebrafish lacking NF-kB/p65. In parallel, ATF6-mediated inhibition of TRIM10/NF-kB signaling shows that endoplasmic reticulum stress modules can directly modulate this immune activation cascade. These examples illustrate why GO:0002757 is a central node for both basic immunology and translational studies of infection, autoimmunity, and cancer.
immune response-activating signaling pathway At A Glance
| GO ID | GO:0002757 |
|---|---|
| GO term | immune response-activating signaling pathway |
| Ontology | biological_process |
| Synonym | immune response-activating signal transduction |
| Definition | The series of molecular signals generated by a ligand binding to its receptor that lead to the activation or perpetuation of an immune response. |
| Major function | Transduces ligand-receptor engagement into transcriptional and post-transcriptional immune effector programs, including cytokine production, inflammasome activation, and antiviral gene expression [1, 5, 6, 7]. |
| Key downstream modules | NF-kB/p65, inflammasome complexes, interferon-stimulated gene networks, and stress-responsive ATF6-TRIM10 signaling [4, 6, 7]. |
| Representative disease links | Severe COVID-19, systemic sclerosis, testicular cancer immune microenvironment, and influenza susceptibility [2, 5, 6, 8]. |
| Common research methods | Single-cell RNA sequencing, blood transcriptome profiling, random forest/artificial neural network modeling, and CRISPR-based perturbation [1, 5, 6]. |
What Is GO:0002757?
In our own words, GO:0002757 describes the entire set of molecular signaling events that begin when a ligand engages its receptor and culminate in the activation or continuation of an immune response. This includes receptor-proximal phosphorylation events, adaptor recruitment, activation of transcription factors such as NF-kB, inflammasome assembly, and the induction of immune effector genes. The term is intentionally broad: it covers signaling initiated by cytokines, pathogen-associated molecular patterns, and other immune ligands, as long as the downstream consequence is immune response activation or perpetuation [1, 5, 6, 7].
Why Is immune response-activating signaling pathway Important in Cell Biology?
GO:0002757 is important because it defines the signaling logic that determines whether an immune response is initiated, sustained, or resolved. Nearly every major immunological outcome, from antiviral defense to tumor immune surveillance, depends on the proper activation of this pathway [1, 5, 7]. When the pathway is too weak, pathogens such as influenza A/H3N2 or SARS-CoV-2 can escape control, as suggested by transcriptomic studies linking baseline immune signaling gene expression to susceptibility and severe COVID-19 [5, 6]. When the pathway is overactive or chronically engaged, it contributes to inflammatory pathology, as seen in systemic sclerosis and in endothelial inflammation after extended hepatectomy [2, 4]. Therefore, understanding GO:0002757 is essential for designing interventions that boost protective immunity without causing collateral tissue damage.
• Defines the receptor-to-transcription cascade that initiates antiviral and antibacterial immunity.
• Baseline activity of this pathway in blood predicts susceptibility to seasonal influenza A/H3N2.
• Inflammasome-related genes within this pathway stratify severe COVID-19 patients and correlate with disease severity.
• NF-kB/p65, a central node of this pathway, is required for antiviral responses in vivo.
• ATF6-mediated inhibition of TRIM10/NF-kB signaling links ER stress to suppression of endothelial inflammation.
• The pathway shapes the immune microenvironment of testicular cancer and may influence immunotherapy response.
• Single-cell profiling of esophageal squamous cell carcinoma shows pathway remodeling after chemo-immunotherapy.
• Baricitinib, a JAK inhibitor, modulates immune signaling in systemic sclerosis, illustrating clinical tractability of this pathway.
• Plant microRNA studies of pathogen defense highlight conserved principles of immune signaling activation across kingdoms.
• CRISPR-based perturbation of pathway nodes enables causal dissection of immune activation in disease models [4, 7].
What Happens During immune response-activating signaling pathway?
Ligand recognition and receptor engagement
In simple terms: An immune signal molecule docks onto a receptor on the cell surface or inside the cell, like a key fitting a lock.
The pathway begins when a ligand, such as a cytokine, pathogen-associated molecular pattern, or damage-associated molecular pattern, binds to its cognate receptor. This binding event triggers conformational changes and clustering of receptor subunits, which is the first committed step of GO:0002757. In antiviral immunity, this step is essential for detecting viral components and initiating downstream signaling, as shown by the requirement for NF-kB/p65 in zebrafish antiviral responses. Transcriptomic studies of influenza susceptibility indicate that baseline expression of receptor-proximal immune signaling genes in blood can predict host outcome, underscoring the importance of this initial recognition step.
Adaptor recruitment and kinase activation
In simple terms: Once the receptor is engaged, adapter proteins and kinases inside the cell are recruited to relay the message.
Following receptor engagement, adaptor proteins are recruited to the receptor cytoplasmic tails, leading to activation of kinases such as IKK and TAK1. These kinases phosphorylate downstream substrates, including IkB, which releases NF-kB to translocate to the nucleus. This step is a critical amplification node in GO:0002757. In severe COVID-19, inflammasome-related genes that function in this phase are differentially expressed and can be used to classify patients with poor outcomes. Similarly, ATF6-mediated inhibition of TRIM10/NF-kB signaling demonstrates that stress-responsive modules can intersect with and modulate this kinase activation phase.
Transcription factor activation and nuclear translocation
In simple terms: The signal enters the nucleus and switches on immune genes.
Activated NF-kB and other transcription factors, such as IRFs and STATs, translocate to the nucleus and bind DNA to initiate transcription of immune response genes. This step represents the conversion of a transient signaling event into a sustained transcriptional program, which is a hallmark of GO:0002757. The essential role of NF-kB/p65 in antiviral responses has been demonstrated in vivo using zebrafish models, where loss of p65 impairs the ability to control viral infection. In testicular cancer, immune score-based analyses have identified novel genes in this pathway that shape the tumor microenvironment.
Inflammasome assembly and cytokine maturation
In simple terms: A molecular platform called the inflammasome assembles and activates inflammatory cytokines.
In parallel with NF-kB activation, some branches of GO:0002757 lead to inflammasome assembly, caspase-1 activation, and maturation of IL-1beta and IL-18. This step is particularly relevant to severe COVID-19, where inflammasome-related gene signatures distinguish patient subgroups and correlate with disease severity. The inflammasome thus represents a critical effector arm of immune response-activating signaling that can perpetuate inflammation if not properly regulated.
Perpetuation and feedback regulation
In simple terms: The immune response keeps itself going through positive feedback and is kept in check by negative regulators.
Once activated, the pathway can perpetuate itself through autocrine and paracrine cytokine loops, as well as through sustained receptor signaling. Negative feedback regulators, including ATF6-TRIM10 and other inhibitory modules, prevent excessive inflammation. In endothelial cells after extended hepatectomy, ATF6 alleviates inflammation by inhibiting TRIM10/NF-kB signaling, illustrating how feedback control within GO:0002757 protects against tissue damage. In systemic sclerosis, baricitinib treatment modulates JAK-dependent cytokine signaling, further highlighting the clinical importance of feedback regulation in this pathway.
Key Genes Involved in GO:0002757 immune response-activating signaling pathway
The following genes and proteins are representative nodes within GO:0002757, supported by the cited literature.
| Gene | Major Role | Research Relevance |
|---|---|---|
| NF-kB/p65 (RELA) | Central transcription factor downstream of receptor signaling | Required for antiviral responses in zebrafish; target for anti-inflammatory strategies |
| TRIM10 | E3 ubiquitin ligase modulating NF-kB signaling | Inhibited by ATF6 to reduce endothelial inflammation after hepatectomy |
| ATF6 | ER stress sensor that suppresses TRIM10/NF-kB signaling | Protective role in endothelial inflammation |
| NLRP3 | Inflammasome sensor forming caspase-1 activation platform | Inflammasome-related gene signatures in severe COVID-19 |
| CASP1 | Caspase-1, executes cytokine maturation in inflammasome | Inflammasome activation in COVID-19 severity |
| IL1B | Pro-inflammatory cytokine matured by inflammasome | Marker of severe COVID-19 and inflammasome activity |
| IL18 | Pro-inflammatory cytokine matured by inflammasome | Inflammasome-related gene in COVID-19 severity models |
| JAK1 | Kinase transducing cytokine receptor signals | Target of baricitinib in systemic sclerosis |
| JAK2 | Kinase transducing cytokine receptor signals | Target of baricitinib in systemic sclerosis |
| STAT1 | Transcription factor downstream of JAK-STAT signaling | Interferon signaling in antiviral immunity [5, 7] |
| STAT3 | Transcription factor downstream of JAK-STAT signaling | Immune signaling in cancer microenvironment |
| IFNAR1 | Type I interferon receptor subunit | Antiviral signaling and influenza susceptibility |
| IFNAR2 | Type I interferon receptor subunit | Antiviral signaling and influenza susceptibility |
| MYD88 | Adaptor protein in TLR/IL-1R signaling | Innate immune activation upstream of NF-kB [6, 7] |
| TRIF (TICAM1) | Adaptor protein in TLR3/4 signaling | Innate immune activation upstream of NF-kB [6, 7] |
| IRF3 | Transcription factor for type I interferon induction | Antiviral gene expression [5, 7] |
| IRF7 | Transcription factor for type I interferon induction | Antiviral gene expression [5, 7] |
| TNF | Pro-inflammatory cytokine amplified by NF-kB | Immune microenvironment and inflammation [4, 8] |
How Is immune response-activating signaling pathway Regulated?
GO:0002757 is regulated at multiple levels. Positive regulation occurs through ligand availability, receptor expression, and kinase amplification loops, while negative regulation is mediated by inhibitory proteins such as ATF6-TRIM10, which suppresses NF-kB signaling in endothelial cells. JAK-STAT signaling, targeted by baricitinib in systemic sclerosis, represents another regulatory layer that modulates cytokine-driven immune activation. Inflammasome activity is controlled by post-translational modifications and by availability of its sensor proteins, as suggested by inflammasome-related gene expression patterns in severe COVID-19. Transcriptomic studies of influenza susceptibility indicate that baseline expression levels of immune signaling genes in blood are associated with subsequent infection risk, implying that homeostatic set points of this pathway are subject to host genetic and environmental regulation. Finally, single-cell profiling of esophageal squamous cell carcinoma after chemo-immunotherapy reveals dynamic regulation of immune signaling modules in the tumor microenvironment.
immune response-activating signaling pathway and Human Disease
| Gene | Disease / Biology | Potential Experimental Model |
|---|---|---|
| NLRP3 | Severe COVID-19 inflammasome activation | Knockout in macrophage cell line followed by SARS-CoV-2 spike stimulation |
| JAK1/JAK2 | Systemic sclerosis cytokine signaling | Point mutation of kinase domain to test baricitinib sensitivity |
| NF-kB/p65 (RELA) | Antiviral defense failure | Knockout zebrafish or mammalian cells challenged with virus |
| TRIM10 | Endothelial inflammation after hepatectomy | Overexpression and knockout in endothelial cells under ATF6 modulation |
| IFNAR1/IFNAR2 | Influenza A/H3N2 susceptibility | Knockout in airway epithelial cells followed by infection |
Severe COVID-19 and inflammasome activation
In severe COVID-19, genes related to inflammasome function within GO:0002757 are differentially expressed and can be used to classify patients with poor outcomes. A joint model using random forest and artificial neural network identified key inflammasome-related genes that distinguish severe from mild disease, highlighting the pathway's role in COVID-19 immunopathology.
Systemic sclerosis and JAK-dependent cytokine signaling
Systemic sclerosis is characterized by chronic immune activation and fibrosis. Baricitinib, a JAK inhibitor, was tested in a prospective randomized trial and modulates cytokine signaling that intersects with GO:0002757, demonstrating clinical tractability of this pathway in autoimmune disease.
Cancer immune microenvironment
In testicular cancer, ESTIMATE algorithm-derived immune scores identified novel genes in immune response-activating signaling that shape the tumor microenvironment. In esophageal squamous cell carcinoma, single-cell profiling of response to neoadjuvant chemo-immunotherapy revealed dynamic changes in immune signaling pathways, suggesting that GO:0002757 activity influences treatment response.
Influenza susceptibility and antiviral defense
Baseline blood transcriptome profiles of immune signaling genes predict susceptibility to seasonal influenza A/H3N2, linking GO:0002757 activity to host defense. In zebrafish, NF-kB/p65 is required for antiviral responses, providing genetic evidence that this pathway is essential for controlling viral infection.
From immune response-activating signaling pathway-Related Genes to Experimental Models
| Research Question | Suitable Model |
|---|---|
| Is NF-kB/p65 required for antiviral responses? | Knockout of RELA in zebrafish or mammalian cells |
| Does TRIM10 mediate ATF6-dependent suppression of NF-kB? | Knockout and overexpression of TRIM10 in endothelial cells |
| Which inflammasome genes predict severe COVID-19? | Knockout of NLRP3, CASP1, IL1B in macrophages followed by transcriptomics |
| Does JAK inhibition modulate systemic sclerosis immune signaling? | Point mutation of JAK1/JAK2 kinase domain in cell lines treated with baricitinib |
| Can baseline immune gene expression predict influenza susceptibility? | Overexpression or knockout of IFNAR1 in airway epithelial cells |
| What genes shape testicular cancer immune microenvironment? | Knock-in of candidate immune genes in testicular cancer cell lines |
How to Study the immune response-activating signaling pathway Process
| Method | What It Measures | Typical Application |
|---|---|---|
| Single-cell RNA sequencing | Cell-type-specific gene expression and pathway activity | Tumor immune microenvironment after immunotherapy |
| Blood transcriptome profiling | Baseline immune gene expression | Predicting influenza susceptibility |
| Random forest / ANN | Feature importance and classification | Identifying severe COVID-19 inflammasome genes |
| CRISPR knockout | Loss-of-function phenotype | Testing requirement of NF-kB/p65 in antiviral defense |
| CRISPR point mutation | Specific amino acid function | Testing kinase domain sensitivity to inhibitors |
| CRISPR knock-in | Tagged or reporter gene expression | Tracking pathway activation in live cells |
| Overexpression | Gain-of-function phenotype | Testing TRIM10 sufficiency in suppressing NF-kB |
| ESTIMATE algorithm | Immune score from bulk transcriptome | Identifying immune-related genes in testicular cancer |
Single-cell RNA sequencing
Single-cell profiling allows mapping of immune response-activating signaling at cellular resolution. In esophageal squamous cell carcinoma, this approach revealed dynamic changes in immune signaling modules after neoadjuvant chemo-immunotherapy, identifying cell populations with distinct pathway activity.
Blood transcriptome profiling
Baseline blood transcriptome analysis can identify individuals susceptible to seasonal influenza A/H3N2 by measuring expression of immune signaling genes within GO:0002757. This method is minimally invasive and suitable for large cohort studies.
Random forest and artificial neural network modeling
Machine learning approaches applied to transcriptomic data can identify key inflammasome-related genes in severe COVID-19. A joint model using random forest and artificial neural network distinguished severe from mild disease based on immune signaling gene expression.
CRISPR-based perturbation and functional validation
CRISPR knockout, point mutation, and overexpression models enable causal testing of individual nodes within GO:0002757. For example, knockout of NF-kB/p65 in zebrafish demonstrated its requirement for antiviral responses, and modulation of ATF6-TRIM10 signaling in endothelial cells revealed a regulatory mechanism.
How CRISPR Can Be Used to Study GO:0002757 immune response-activating signaling pathway
Knockout
CRISPR knockout is used to delete genes within GO:0002757 to test their requirement for immune activation. For example, knockout of NF-kB/p65 in zebrafish demonstrated its essential role in antiviral responses. Knockout of inflammasome components such as NLRP3 or CASP1 in macrophages can reveal their contribution to COVID-19-associated cytokine release.
Point Mutation
Point mutation models introduce specific amino acid changes to dissect domain functions. For instance, mutating the kinase domain of JAK1 or JAK2 can test sensitivity to baricitinib in systemic sclerosis models. Such models are valuable for understanding how single residues affect signaling output within GO:0002757.
Knock-in
Knock-in models can introduce tagged versions of pathway proteins or reporter genes to track activation in real time. For example, knocking in a fluorescent reporter downstream of NF-kB would allow monitoring of immune response-activating signaling in live cells [4, 7].
Overexpression
Overexpression models test gain-of-function effects. Overexpressing TRIM10 in endothelial cells can suppress NF-kB signaling, mimicking ATF6-mediated inhibition. Overexpressing IFNAR1 or IFNAR2 in airway epithelial cells can enhance antiviral signaling and alter influenza susceptibility.
How EDITGENE Supports immune response-activating signaling pathway Research
Researchers studying immune response-activating signaling pathway-related genes often need to determine whether a candidate gene is causally involved in immune activation or simply correlated with it. EDITGENE provides a comprehensive suite of CRISPR-based services to enable such causal studies, from knockout to knock-in and library screening.
Contact EDITGENE today to design your custom CRISPR model for immune response-activating signaling pathway research.
Frequently Asked Questions About immune response-activating signaling pathway
What is GO:0002757 immune response-activating signaling pathway?
GO:0002757 is a Gene Ontology biological process term defined as the series of molecular signals generated by a ligand binding to its receptor that lead to the activation or perpetuation of an immune response [1, 5].
What genes are involved in immune response-activating signaling pathway?
Key genes include NF-kB/p65 (RELA), TRIM10, ATF6, NLRP3, CASP1, IL1B, IL18, JAK1, JAK2, STAT1, STAT3, IFNAR1, IFNAR2, MYD88, TRIF, IRF3, IRF7, and TNF, as supported by studies in antiviral immunity, COVID-19, and cancer [4, 5, 6, 7, 8].
How is immune response-activating signaling pathway regulated?
It is regulated by positive feedback through cytokines and kinases, and by negative regulators such as ATF6-TRIM10 that suppress NF-kB signaling. JAK-STAT signaling is another regulatory layer targeted by baricitinib.
What diseases are associated with GO:0002757?
Severe COVID-19, systemic sclerosis, testicular cancer, esophageal squamous cell carcinoma, and influenza susceptibility have been linked to this pathway [1, 2, 5, 6, 8].
How can I study immune response-activating signaling pathway in the lab?
Common methods include single-cell RNA sequencing, blood transcriptome profiling, machine learning modeling, and CRISPR-based perturbation such as knockout or overexpression [1, 4, 5, 6, 7].
What is the role of NF-kB in immune response-activating signaling?
NF-kB/p65 is a central transcription factor downstream of receptor signaling and is required for antiviral responses in vivo.
How does the inflammasome contribute to GO:0002757?
The inflammasome assembles in response to immune signals and activates caspase-1 to mature IL-1beta and IL-18, perpetuating inflammation; inflammasome-related genes are key markers in severe COVID-19.
Can CRISPR be used to study immune response-activating signaling pathway?
Yes, CRISPR knockout, point mutation, knock-in, and overexpression models allow causal testing of individual pathway nodes, as demonstrated for NF-kB/p65 and TRIM10 [4, 7].
What is the difference between GO:0002757 and other immune GO terms?
GO:0002757 specifically covers the signaling events from ligand-receptor binding to immune response activation or perpetuation, rather than the immune response itself or individual effector functions [1, 5].
Why is baseline immune gene expression important for influenza susceptibility?
Blood transcriptome studies show that baseline expression levels of immune signaling genes predict susceptibility to seasonal influenza A/H3N2, linking pathway activity to host outcome.
Conclusion
GO:0002757 immune response-activating signaling pathway is a central biological process that converts ligand-receptor engagement into sustained immune activation. Its components, including NF-kB, inflammasome, and JAK-STAT modules, are critical for antiviral defense, cancer immunity, and inflammatory disease pathogenesis [1, 2, 4, 5, 6, 7, 8]. Understanding this pathway requires integrating transcriptomic, single-cell, and CRISPR-based functional approaches. EDITGENE provides the tools to dissect this pathway causally and translate findings into therapeutic hypotheses.
References
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- 2. Chen F et al.. 2025. BAricitinib in patients with SystemIC Sclerosis (BASICS): a prospective, open-label, randomised trial.. Clin Rheumatol 44(7):2861-2871 PMID: 40381085
- 3. Luo C et al.. 2024. Plant microRNAs regulate the defense response against pathogens.. Front Microbiol 15:1434798 PMID: 39282567
- 4. Shi CC et al.. 2025. ATF6 Alleviates Endothelial Inflammation Following Extended Hepatectomy Through Inhibition of TRIM10/NF-κB Signaling.. FASEB J 39(16):e70933 PMID: 40801087
- 5. Tang J et al.. 2022. Susceptibility identification for seasonal influenza A/H3N2 based on baseline blood transcriptome.. Front Immunol 13:1048774 PMID: 36713410
- 6. Ou H et al.. 2023. Identifying key genes related to inflammasome in severe COVID-19 patients based on a joint model with random forest and artificial neural network.. Front Cell Infect Microbiol 13:1139998 PMID: 37113134
- 7. Ouyang G et al.. 2020. Zebrafish NF-κB/p65 Is Required for Antiviral Responses.. J Immunol 204(11):3019-3029 PMID: 32321758
- 8. Ke ZB et al.. 2021. Identification of novel genes in testicular cancer microenvironment based on ESTIMATE algorithm-derived immune scores.. J Cell Physiol 236(1):706-713 PMID: 32617980
