Butyrophilin subfamily 3 member A3 (BTN3A3, also known as BTF3) is a type I transmembrane protein belonging to the extended B7 family of immune regulatory molecules. It contains two extracellular immunoglobulin domains and an intracellular B30.2 (PRYSPRY) domain. BTN3A3 plays a role in T cell-mediated immunity, particularly in the regulation of Vgamma9Vdelta2 T cells, though it is less functionally active than its close paralog BTN3A1. The protein forms homodimers and can heterodimerize with BTN3A1, regulating immune responses and potentially contributing to cancer biology.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
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GO:0001817
regulation of cytokine production
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IBA
GO_REF:0000033 |
KEEP AS NON CORE |
Summary: IBA annotation for regulation of cytokine production. This is a general biological process annotation that may apply more to BTN3A1 than BTN3A3. The deep research suggests BTN3A3 has roles in immune regulation but does not provide specific evidence that BTN3A3 directly regulates cytokine production.
Reason: While BTN3A3 is involved in immune responses and T cell-mediated immunity, the specific evidence for regulation of cytokine production is limited for BTN3A3 specifically. This annotation likely derives from phylogenetic inference based on BTN3A1, which has more direct experimental evidence for this function. BTN3A3 appears to have a supporting rather than primary role in T cell activation, which may indirectly affect cytokine production. Marking as non-core pending more specific experimental evidence.
Supporting Evidence:
file:human/BTN3A3/BTN3A3-deep-research-perplexity-lite.md
BTN3A3 functions as a signaling receptor and is involved in immune regulation, particularly in T-cell responses. Its molecular functions include: Signaling receptor binding, Regulation of cytokine production, T cell-mediated immunity
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GO:0005102
signaling receptor binding
|
IBA
GO_REF:0000033 |
MODIFY |
Summary: IBA annotation for signaling receptor binding. BTN3A3 can bind to other BTN3A family members and potentially to receptors on T cells, consistent with its role in immune signaling.
Reason: The term "signaling receptor binding" (GO:0005102) is too vague and does not capture the specific molecular function of BTN3A3. The protein has more specific functions related to immune receptor activity and protein heterodimerization. BTN3A3 acts as an immune regulatory molecule that can interact with BTN3A1 and BTN3A2 through its IgC domain to form heterodimers. A more informative term would be immune receptor activity or protein heterodimerization activity.
Proposed replacements:
immune receptor activity
protein heterodimerization activity
Supporting Evidence:
PMID:29339503
BTN3A3 could also be coimmunoprecipitated with BTN3A1 (Fig. S3A), consistent with its potential to functionally collaborate with BTN3A1 in the absence of BTN3A2 (Fig. 1D).
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GO:0009897
external side of plasma membrane
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IBA
GO_REF:0000033 |
ACCEPT |
Summary: IBA annotation for external side of plasma membrane. BTN3A3 is a type I transmembrane protein with extracellular immunoglobulin domains that face the external side of the membrane.
Reason: This annotation is correct and well-supported. BTN3A3 is a type I transmembrane protein with two extracellular Ig domains (IgV and IgC) that extend to the external side of the plasma membrane. UniProt confirms this topology with extracellular domain from residues 30-248. This is consistent with its function as an immune regulatory molecule that interacts with other cell surface proteins and potentially with T cell receptors.
Supporting Evidence:
file:human/BTN3A3/BTN3A3-deep-research-perplexity-lite.md
BTN3A3 is a type I membrane protein, meaning it is anchored in the plasma membrane with its N-terminus extracellular and C-terminus intracellular
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GO:0050852
T cell receptor signaling pathway
|
IBA
GO_REF:0000033 |
KEEP AS NON CORE |
Summary: IBA annotation for T cell receptor signaling pathway. BTN3A3 has been shown to play a role in T cell responses, though the experimental evidence is stronger for BTN3A1.
Reason: BTN3A3 is involved in T cell-mediated immunity and can modulate T cell responses, but the primary functional molecule in this pathway is BTN3A1. BTN3A3 appears to play a supporting role, potentially through heterodimerization with BTN3A1. PMID:22767497 demonstrated the key role of CD277/BTN3A in T cell responses, but focused primarily on the BTN3A1 isoform for PAg sensing. BTN3A3 may contribute to TCR signaling indirectly through its interactions with BTN3A1.
Supporting Evidence:
PMID:22767497
Vγ9Vδ2 T-cell activation by agonist anti-CD277 mAbs was restored after re-expression of any of the 3 CD277 isoforms, responses to PAg or NBP were obtained after re-expression of BTN3A1 only.
file:human/BTN3A3/BTN3A3-deep-research-perplexity-lite.md
T cell receptor signaling pathway
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GO:0002250
adaptive immune response
|
IEA
GO_REF:0000043 |
ACCEPT |
Summary: IEA annotation based on UniProtKB keyword mapping for adaptive immune response. This is appropriately general for BTN3A3 role in immunity.
Reason: This annotation is correct at an appropriate level of generality. BTN3A3 plays a role in adaptive immunity through its involvement in T cell-mediated immune responses. As a member of the butyrophilin family within the extended B7 superfamily, it contributes to immune regulation. The annotation is supported by UniProt function annotation stating it plays a role in T-cell responses in the adaptive immune response.
Supporting Evidence:
file:human/BTN3A3/BTN3A3-deep-research-perplexity-lite.md
Adaptive immune response
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GO:0002376
immune system process
|
IEA
GO_REF:0000043 |
ACCEPT |
Summary: IEA annotation for immune system process. This is a very general parent term that is clearly correct for BTN3A3.
Reason: This is an appropriately general annotation for BTN3A3, which is clearly involved in immune system processes through its role in T cell regulation and adaptive immunity. While this term is very broad, it accurately captures the biological context of BTN3A3 function. The term is a parent of more specific terms like adaptive immune response and T cell mediated immunity.
Supporting Evidence:
file:human/BTN3A3/BTN3A3-deep-research-perplexity-lite.md
BTN3A3 is involved in several critical biological processes: T cell-mediated immunity, Regulation of cytokine production, Immune response modulation
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GO:0005886
plasma membrane
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IEA
GO_REF:0000044 |
ACCEPT |
Summary: IEA annotation based on UniProtKB subcellular location mapping. BTN3A3 is correctly annotated to plasma membrane.
Reason: This annotation is correct. BTN3A3 is a type I transmembrane protein that localizes to the plasma membrane as confirmed by UniProt and multiple experimental studies. The protein has a signal peptide (residues 1-29), extracellular domain (30-248), transmembrane helix (249-269), and cytoplasmic domain (270-584). Cell membrane localization was confirmed experimentally by PMID:22767497.
Supporting Evidence:
file:human/BTN3A3/BTN3A3-deep-research-perplexity-lite.md
Plasma membrane
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GO:0005515
protein binding
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IPI
PMID:29339503 Heteromeric interactions regulate butyrophilin (BTN) and BTN... |
MODIFY |
Summary: IPI annotation for protein binding based on BTN3A1 interaction. This term is too vague per curation guidelines.
Reason: While the evidence from PMID:29339503 clearly demonstrates that BTN3A3 binds to BTN3A1, the term "protein binding" (GO:0005515) is explicitly discouraged in the curation guidelines as it does not provide informative functional information. The specific interaction demonstrated is protein heterodimerization, which is a more informative molecular function term. BTN3A3 forms heterodimers with BTN3A1 to regulate immune responses.
Proposed replacements:
protein heterodimerization activity
Supporting Evidence:
PMID:29339503
BTN3A3 could also be coimmunoprecipitated with BTN3A1 (Fig. S3A), consistent with its potential to functionally collaborate with BTN3A1 in the absence of BTN3A2 (Fig. 1D).
|
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GO:0005515
protein binding
|
IPI
PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... |
MODIFY |
Summary: IPI annotation for protein binding from a proteome-scale interactome study. This term is too vague per curation guidelines.
Reason: PMID:33961781 is a large-scale proteomics study mapping cell-specific protein-protein interactions. While it likely identified BTN3A3 interactions, the generic term "protein binding" does not provide useful functional information per curation guidelines. Without access to the specific interaction partners identified in this study, and given that we have better characterized interactions with BTN3A1 from PMID:29339503, this annotation should be replaced with the more specific protein heterodimerization activity term.
Proposed replacements:
protein heterodimerization activity
Supporting Evidence:
PMID:33961781
Thousands of interactions assemble proteins into modules that impart spatial and functional organization to the cellular proteome
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GO:0005886
plasma membrane
|
TAS
Reactome:R-HSA-8851038 |
ACCEPT |
Summary: TAS annotation from Reactome pathway for BTN3A1 binding prenylated phosphoantigens. This pathway primarily describes BTN3A1, not BTN3A3.
Reason: While the Reactome pathway R-HSA-8851038 focuses on BTN3A1 binding to prenylated phosphoantigens, BTN3A3 is also a plasma membrane protein as established by multiple lines of evidence. The localization annotation is correct even if the specific Reactome pathway is more relevant to BTN3A1. BTN3A3 is present at the plasma membrane as a type I transmembrane protein.
Supporting Evidence:
file:human/BTN3A3/BTN3A3-deep-research-perplexity-lite.md
Plasma membrane
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GO:0016020
membrane
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HDA
PMID:19946888 Defining the membrane proteome of NK cells. |
ACCEPT |
Summary: HDA annotation from high-throughput detection study of NK cell membrane proteome. This is a very general parent term.
Reason: PMID:19946888 is a proteomics study defining the membrane proteome of NK cells, which detected BTN3A3. The annotation to the general term "membrane" (GO:0016020) is correct, though less specific than plasma membrane. BTN3A3 is indeed an integral membrane protein. This annotation can coexist with the more specific plasma membrane annotations.
Supporting Evidence:
file:human/BTN3A3/BTN3A3-deep-research-perplexity-lite.md
Integral component of the membrane
PMID:19946888
The present study was initiated to define the composition of the membrane proteome of the Natural Killer (NK) like cell line YTS
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GO:0002456
T cell mediated immunity
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IMP
PMID:22767497 Key implication of CD277/butyrophilin-3 (BTN3A) in cellular ... |
ACCEPT |
Summary: IMP annotation for T cell mediated immunity from key experimental study. This is a core function, though primarily demonstrated for BTN3A1.
Reason: PMID:22767497 is the key study demonstrating the role of CD277/BTN3A molecules in Vγ9Vδ2 T cell activation by phosphoantigens. The study showed that CD277 knockdown and domain-shuffling approaches confirmed the implication of BTN3A1 in PAg sensing, and that antibody 20.1 against CD277 (which recognizes all three BTN3A isoforms) can activate T cells. While BTN3A1 is the primary functional isoform, BTN3A3 contributes to T cell-mediated immunity through its expression and potential collaborative functions with BTN3A1. The IMP evidence code indicates this was demonstrated by mutant phenotype analysis.
Supporting Evidence:
PMID:22767497
This study demonstrates a novel role played by B7-like molecules in human γδ T-cell antigenic activation
file:human/BTN3A3/BTN3A3-deep-research-perplexity-lite.md
T cell-mediated immunity
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GO:0005886
plasma membrane
|
IDA
PMID:22767497 Key implication of CD277/butyrophilin-3 (BTN3A) in cellular ... |
ACCEPT |
Summary: IDA annotation for plasma membrane with direct experimental evidence from PMID:22767497.
Reason: PMID:22767497 provides direct experimental evidence (IDA) for plasma membrane localization of BTN3A proteins including BTN3A3. The study included confocal microscopy and flow cytometry demonstrating cell surface expression. UniProt also confirms that BTN3A3 subcellular location was determined in this study. This is strong experimental evidence for plasma membrane localization.
Supporting Evidence:
file:human/BTN3A3/BTN3A3-deep-research-perplexity-lite.md
Plasma membrane
PMID:22767497
We show that treatment of nonsusceptible target cells with antibody 20.1 against CD277, a member of the extended B7 superfamily related to butyrophilin, mimics PAg-induced Vγ9Vδ2 T-cell activation
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Research report: BTN3A3 (Butyrophilin subfamily 3 member A3) — human (UniProt O00478)
Identity verification and gene context
- Identity: BTN3A3 encodes a primate-specific, type I transmembrane immunoglobulin superfamily protein in the BTN/MOG family. Human BTN3A3 is one of three BTN3A paralogs (BTN3A1, BTN3A2, BTN3A3) encoded in the extended MHC locus. BTN3A3 contains extracellular IgV and IgC domains and an intracellular B30.2/SPRY domain; BTN3A2 lacks the B30.2 domain, whereas BTN3A1 and BTN3A3 possess it (human) (Nature Communications, 2023; https://doi.org/10.1038/s41467-023-41938-8, published Nov 2023) (karunakaran2023adistincttopology pages 1-2). A cautionary note: some databases list “BTF3” as a synonym of BTN3A3; this should not be confused with the unrelated transcription factor gene BTF3. All evidence below pertains to human BTN3A3 with BTN/MOG immunoglobulin architecture.
Key concepts and definitions
- Architecture/domains: BTN3A3 is a single-pass type I transmembrane protein with an N-terminal IgV-like domain, a membrane-proximal IgC-like domain, a transmembrane helix, a juxtamembrane (JM) segment, and a C-terminal intracellular B30.2/SPRY domain (Nature Communications, 2023; https://doi.org/10.1038/s41467-023-41938-8) (karunakaran2023adistincttopology pages 1-2).
- Family roles: BTN3A molecules collaborate with BTN2A1 to regulate activation of human Vγ9Vδ2 T cells in response to phosphoantigens (PAgs). Although BTN3A1’s B30.2 binds PAgs, BTN3A3’s B30.2 differs and is not competent for direct PAg binding (see Mechanisms below) (Nature Communications, 2023; https://doi.org/10.1038/s41467-023-41938-8; Current Oncology, 2025; https://doi.org/10.3390/curroncol32060329) (karunakaran2023adistincttopology pages 1-2, tang2025mechanismsandfunctions pages 5-6).
Cellular and tissue localization
- Tissue distribution: BTN3A3 is constitutively expressed in the human respiratory tract. Immunohistochemistry in human tissues shows BTN3A3-positive cells along the nasal epithelium, and expression in airway epithelial cells (including type I/II pneumocytes), alveolar macrophages, and endothelial cells. Lung has among the highest BTN3A3 expression across surveyed tissues (Nature, 2023; https://doi.org/10.1038/s41586-023-06261-8, published Jun 2023) (pinto2023btn3a3evasionpromotes pages 1-5, pinto2023btn3a3evasionpromotes pages 35-37).
- Inducibility: BTN3A3 can be upregulated by type I/II interferons in human cells (Nature, 2023; https://doi.org/10.1038/s41586-023-06261-8; MedComm, 2023; https://doi.org/10.1002/mco2.441) (pinto2023btn3a3evasionpromotes pages 1-5, tian2023thedeterminantsassociated pages 1-3).
Mechanisms and pathways
A. γδ T cell activation (Vγ9Vδ2)
- Division of labor within BTN3A complexes: PAg sensing occurs on the intracellular B30.2 domain of BTN3A1, but the extracellular IgV domain of BTN3A2/BTN3A3 contributes to Vγ9Vδ2 TCR triggering. Mechanistic data indicate that positioning the relevant intracellular and extracellular domains on different BTN3A chains within homo-/heteromers is required for optimal activation. JM-region interactions regulate BTN3A homo-/heteromer formation, trafficking, and conformation, thereby tuning signaling (Nature Communications, 2023; https://doi.org/10.1038/s41467-023-41938-8) (karunakaran2023adistincttopology pages 1-2).
- BTN3A3’s B30.2 and PAg binding: Unlike BTN3A1, BTN3A3’s B30.2 domain does not directly bind PAgs; a single residue difference at position 351 (Arg in BTN3A3 vs His in BTN3A1) disrupts the positively charged binding pocket required for PAg binding. BTN3A3 nonetheless participates via its extracellular domain within BTN3A complexes that engage the Vγ9Vδ2 TCR (Current Oncology, 2025; https://doi.org/10.3390/curroncol32060329) (tang2025mechanismsandfunctions pages 5-6).
B. Antiviral restriction of influenza A viruses
- Primary activity and species specificity: BTN3A3 is a potent, primate-evolved host restriction factor that inhibits avian (but not most human-adapted) influenza A viruses (IAV) by blocking early viral RNA replication. In cell-based ISG screens, BTN3A3 (and BTN3A1 to a lesser extent) restricted avian H1N1 replication, while human-adapted strains (e.g., PR8, Cal04) were largely unaffected. siRNA depletion of BTN3A3 increased replication of avian strains in human airway-derived cells (Nature, 2023; https://doi.org/10.1038/s41586-023-06261-8) (pinto2023btn3a3evasionpromotes pages 1-5, pinto2023btn3a3evasionpromotes pages 35-37).
- Viral genetic determinants of evasion: The viral nucleoprotein (NP) residue 313 determines sensitivity: avian viruses commonly encode 313F (or 313L), which confers BTN3A3 sensitivity, whereas human viruses often encode 313Y or 313V, conferring evasion. Additional substitutions at NP residue 52 (adjacent to 313) in some avian zoonotic lineages (e.g., H7, H9) also mediate evasion in humans (Nature, 2023; https://doi.org/10.1038/s41586-023-06261-8; MedComm, 2023; https://doi.org/10.1002/mco2.441) (pinto2023btn3a3evasionpromotes pages 1-5, tian2023thedeterminantsassociated pages 1-3).
- Magnitude and stage of restriction: Overexpression of BTN3A3 in human A549 cells produced large reductions in infectious titers of an avian H1N1 strain; BTN3A3’s inhibitory effect was reported to be orders of magnitude greater than BTN3A1 in this system, acting early at viral RNA replication (MedComm, 2023; https://doi.org/10.1002/mco2.441) (tian2023thedeterminantsassociated pages 1-3).
- Interferon connection and airway relevance: BTN3A3 is constitutively present in human airways and can be further induced by type I/II IFNs, positioning it as a component of the human species barrier to avian IAV spillover (Nature, 2023; https://doi.org/10.1038/s41586-023-06261-8) (pinto2023btn3a3evasionpromotes pages 1-5, pinto2023btn3a3evasionpromotes pages 35-37).
Recent developments and latest research (prioritizing 2023–2024)
- Nature 2023 (Pinto et al.): Established BTN3A3 as a primate-evolved, airway-expressed restriction factor against avian IAV; mapped viral NP residue 313 and nearby residue 52 as evasion determinants; showed early block of avian IAV RNA replication; documented constitutive airway expression and IFN inducibility (https://doi.org/10.1038/s41586-023-06261-8; Jun 2023) (pinto2023btn3a3evasionpromotes pages 1-5, pinto2023btn3a3evasionpromotes pages 35-37).
- Nature Communications 2023 (Karunakaran et al.): Demonstrated BTN3A3’s extracellular domain contribution to Vγ9Vδ2 activation, the necessity of correct domain partition across BTN3A chains, and the role of JM-region interactions in BTN3A complex formation and function (https://doi.org/10.1038/s41467-023-41938-8; Nov 2023) (karunakaran2023adistincttopology pages 1-2).
- MedComm 2023 (Tian et al.): Reviewed the impact of NP residue mutations (313 F/L→Y/V; and residue 52 N/H/Q) for BTN3A3 evasion and summarized experimental evidence of BTN3A3’s potency vs avian IAV in human cells (https://doi.org/10.1002/mco2.441; Dec 2023) (tian2023thedeterminantsassociated pages 1-3).
- Current Oncology 2025 review (Tang et al.): Summarized BTN3A3’s structural constraints for PAg binding (Arg351) and its role together with BTN3A1/BTN3A2 in Vγ9Vδ2 activation via heteromeric BTN complexes (https://doi.org/10.3390/curroncol32060329; Jun 2025) (tang2025mechanismsandfunctions pages 5-6).
Current applications and implementations
- γδ T cell biology and immuno-oncology context: Mechanistic insights into BTN3A complexes (BTN3A1/BTN3A2/BTN3A3 with BTN2A1) are foundational for γδ T cell–directed approaches. BTN3A3 participates structurally (extracellular domain) in complexes that engage the Vγ9Vδ2 TCR, although BTN3A1 provides the intracellular PAg sensor. Thus, BTN3A3 is a component of the emerging “BTN axis” targeted for modulating Vγ9Vδ2 responses in cancer and infection (Nature Communications, 2023; https://doi.org/10.1038/s41467-023-41938-8; Current Oncology, 2025; https://doi.org/10.3390/curroncol32060329) (karunakaran2023adistincttopology pages 1-2, tang2025mechanismsandfunctions pages 5-6).
- Public health relevance: BTN3A3 constitutes part of the human innate barrier to avian IAV zoonosis. Viral adaptation at NP 313/52 that evades BTN3A3 correlates with zoonotic potential in certain avian lineages (Nature, 2023; https://doi.org/10.1038/s41586-023-06261-8; MedComm, 2023; https://doi.org/10.1002/mco2.441) (pinto2023btn3a3evasionpromotes pages 1-5, tian2023thedeterminantsassociated pages 1-3).
Expert opinions and authoritative analyses
- Pinto et al. (Nature 2023) provided primary experimental evidence and an evolutionary perspective on BTN3A3 as a primate-evolved restriction factor shaping the IAV species barrier (https://doi.org/10.1038/s41586-023-06261-8) (pinto2023btn3a3evasionpromotes pages 1-5, pinto2023btn3a3evasionpromotes pages 35-37).
- Karunakaran et al. (Nature Communications 2023) clarified the cooperative architecture of BTN3A complexes driving Vγ9Vδ2 activation, highlighting BTN3A3’s extracellular role and JM-region governed assembly (https://doi.org/10.1038/s41467-023-41938-8) (karunakaran2023adistincttopology pages 1-2).
- Tang et al. (Current Oncology 2025) reviewed the molecular basis preventing BTN3A3’s B30.2 domain from binding PAgs (Arg351) and summarized BTN cooperation in γδ T cell activation (https://doi.org/10.3390/curroncol32060329) (tang2025mechanismsandfunctions pages 5-6).
Relevant statistics and data
- ISG screening and functional assays: In human airway-derived cells, BTN3A3 overexpression strongly suppressed replication of avian H1N1, while siRNA knockdown enhanced avian-virus replication without affecting human-adapted PR8. Infection kinetics and western blots confirmed early replication inhibition (Nature, 2023; https://doi.org/10.1038/s41586-023-06261-8) (pinto2023btn3a3evasionpromotes pages 35-37, pinto2023btn3a3evasionpromotes pages 1-5).
- Magnitude of restriction: In A549 cells, BTN3A3 reduced avian IAV titers by large factors; BTN3A3 was reported as markedly more potent than BTN3A1 against an avian H1N1 reporter virus, with orders-of-magnitude reduction in titers (MedComm, 2023; https://doi.org/10.1002/mco2.441) (tian2023thedeterminantsassociated pages 1-3).
- Genetic determinants in NP: Sensitivity vs evasion mapped to NP residue 313 (F/L→Y/V) and nearby residue 52 substitutions (N/H/Q) on the NP head surface (Nature, 2023; https://doi.org/10.1038/s41586-023-06261-8; MedComm, 2023; https://doi.org/10.1002/mco2.441) (pinto2023btn3a3evasionpromotes pages 1-5, tian2023thedeterminantsassociated pages 1-3).
Clinical and disease associations (evidence to date)
- Hematologic malignancy context: Butyrophilin transcripts, including BTN3A family members, are dysregulated in PBMCs and bone marrow of AML patients; broader BTN family studies link BTN pathways to γδ T cell–based immunotherapies. Reports summarized in AML context indicate BTN3A-axis modulation can influence Vγ9Vδ2 cytotoxicity (Acta Haematologica Polonica, 2025; https://doi.org/10.5603/ahp.106632) (jakubik2025butyrophilinsaresignificantly pages 15-17).
- Solid tumor notes: Secondary literature aggregated in AML review indicates that low BTN3A3 expression has been associated with poor prognosis and pro-tumor phenotypes in non-small cell lung cancer in independent studies; however, these are not primary data within that review and should be interpreted cautiously pending direct validation (Acta Haematologica Polonica, 2025; https://doi.org/10.5603/ahp.106632) (jakubik2025butyrophilinsaresignificantly pages 15-17).
Open questions and regulatory insights
- Interferon regulation: BTN3A3 is interferon-inducible in human airway cells; the upstream transcriptional circuitry (e.g., NLRC5, CIITA) and post-translational regulation (e.g., pyroglutamate modification) have been discussed in the broader BTN3A literature, but direct, BTN3A3-specific recent primary evidence was not retrieved in the sources synthesized here (Nature, 2023; https://doi.org/10.1038/s41586-023-06261-8) (pinto2023btn3a3evasionpromotes pages 1-5, pinto2023btn3a3evasionpromotes pages 35-37).
- Structural biochemistry: BTN3A3’s extracellular domain supports Vγ9Vδ2 activation within BTN complexes, whereas its B30.2 domain does not bind PAg, consistent with residue-level constraints (Arg351). The precise stoichiometry and dynamics of BTN3A3-containing complexes at the cell surface alongside BTN2A1 remain active areas of research (Nature Communications, 2023; https://doi.org/10.1038/s41467-023-41938-8; Current Oncology, 2025; https://doi.org/10.3390/curroncol32060329) (karunakaran2023adistincttopology pages 1-2, tang2025mechanismsandfunctions pages 5-6).
Summary of primary function, localization, and pathway role
- Primary function: BTN3A3 is a structural/signaling component of BTN heteromeric complexes that enable Vγ9Vδ2 T cell activation, operating chiefly through its extracellular IgV domain in cooperation with BTN3A1 (intracellular PAg sensor) and BTN2A1 (TCR-binding partner). BTN3A3 also acts as an innate restriction factor against avian IAV, blocking early RNA replication (Nature Communications, 2023; https://doi.org/10.1038/s41467-023-41938-8; Nature, 2023; https://doi.org/10.1038/s41586-023-06261-8) (karunakaran2023adistincttopology pages 1-2, pinto2023btn3a3evasionpromotes pages 1-5, pinto2023btn3a3evasionpromotes pages 35-37).
- Cellular site of action: Plasma membrane (extracellular IgV/IgC domains) for γδ T cell interactions; intracellular B30.2 domain is present but does not bind PAg in BTN3A3. Antiviral restriction is exerted in infected cells of the human airway, with evidence for an intracellular block in avian IAV RNA replication (Nature Communications, 2023; https://doi.org/10.1038/s41467-023-41938-8; Nature, 2023; https://doi.org/10.1038/s41586-023-06261-8) (karunakaran2023adistincttopology pages 1-2, pinto2023btn3a3evasionpromotes pages 1-5).
- Pathways: BTN3A3 contributes to the BTN3A/BTN2A1 axis that transduces PAg-induced “inside-out” signals to the Vγ9Vδ2 TCR. Independently, BTN3A3 is part of IFN-inducible and constitutive epithelial defenses shaping the IAV species barrier (Nature Communications, 2023; https://doi.org/10.1038/s41467-023-41938-8; Nature, 2023; https://doi.org/10.1038/s41586-023-06261-8) (karunakaran2023adistincttopology pages 1-2, pinto2023btn3a3evasionpromotes pages 1-5).
Limitations of current evidence
- Some regulatory features (e.g., specific transcription factors, post-translational modifications) and therapeutic implementations (BTN3A-targeting antibodies) are not directly evidenced in the cited 2023–2024 sources compiled here. Where noted above, such topics require additional source confirmation.
References (with URLs and publication dates)
- Pinto et al. BTN3A3 evasion promotes the zoonotic potential of influenza A viruses. Nature. Published Jun 2023. https://doi.org/10.1038/s41586-023-06261-8 (pinto2023btn3a3evasionpromotes pages 1-5, pinto2023btn3a3evasionpromotes pages 35-37).
- Karunakaran et al. A distinct topology of BTN3A IgV and B30.2 domains controlled by juxtamembrane regions favors optimal human γδ T cell phosphoantigen sensing. Nature Communications. Published Nov 2023. https://doi.org/10.1038/s41467-023-41938-8 (karunakaran2023adistincttopology pages 1-2).
- Tian et al. The determinants associated with zoonotic potential of influenza A viruses: BTN3A3 evasion mediated by residue mutation in the nucleoprotein. MedComm. Published Dec 2023. https://doi.org/10.1002/mco2.441 (tian2023thedeterminantsassociated pages 1-3).
- Tang et al. Mechanisms and Functions of γδ T Cells in Tumor Cell Recognition. Current Oncology. Published Jun 2025. https://doi.org/10.3390/curroncol32060329 (tang2025mechanismsandfunctions pages 5-6).
- Jakubik & Zarobkiewicz. Butyrophilins are significantly dysregulated in the peripheral blood mononuclear cells and bone marrow of acute myeloid leukaemia patients. Acta Haematologica Polonica. Published Oct 2025. https://doi.org/10.5603/ahp.106632 (jakubik2025butyrophilinsaresignificantly pages 15-17).
References
(karunakaran2023adistincttopology pages 1-2): Mohindar M. Karunakaran, Hariharan Subramanian, Yiming Jin, Fiyaz Mohammed, Brigitte Kimmel, Claudia Juraske, Lisa Starick, Anna Nöhren, Nora Länder, Carrie R. Willcox, Rohit Singh, Wolfgang W. Schamel, Viacheslav O. Nikolaev, Volker Kunzmann, Andrew J. Wiemer, Benjamin E. Willcox, and Thomas Herrmann. A distinct topology of btn3a igv and b30.2 domains controlled by juxtamembrane regions favors optimal human γδ t cell phosphoantigen sensing. Nature Communications, Nov 2023. URL: https://doi.org/10.1038/s41467-023-41938-8, doi:10.1038/s41467-023-41938-8. This article has 43 citations and is from a highest quality peer-reviewed journal.
(tang2025mechanismsandfunctions pages 5-6): Jing Tang, Chen Wu, Jintong Na, Yamin Deng, Simin Qin, Liping Zhong, and Yongxiang Zhao. Mechanisms and functions of γδ t cells in tumor cell recognition. Current Oncology, 32:329, Jun 2025. URL: https://doi.org/10.3390/curroncol32060329, doi:10.3390/curroncol32060329. This article has 0 citations and is from a poor quality or predatory journal.
(pinto2023btn3a3evasionpromotes pages 1-5): Rute Maria Pinto, Siddharth Bakshi, Spyros Lytras, Mohammad Khalid Zakaria, Simon Swingler, Julie C. Worrell, Vanessa Herder, Kerrie E. Hargrave, Margus Varjak, Natalia Cameron-Ruiz, Mila Collados Rodriguez, Mariana Varela, Arthur Wickenhagen, Colin Loney, Yanlong Pei, Joseph Hughes, Elise Valette, Matthew L. Turnbull, Wilhelm Furnon, Quan Gu, Lauren Orr, Aislynn Taggart, Ola Diebold, Chris Davis, Chris Boutell, Finn Grey, Edward Hutchinson, Paul Digard, Isabella Monne, Sarah K. Wootton, Megan K. L. MacLeod, Sam J. Wilson, and Massimo Palmarini. Btn3a3 evasion promotes the zoonotic potential of influenza a viruses. Nature, 619:338-347, Jun 2023. URL: https://doi.org/10.1038/s41586-023-06261-8, doi:10.1038/s41586-023-06261-8. This article has 107 citations and is from a highest quality peer-reviewed journal.
(pinto2023btn3a3evasionpromotes pages 35-37): Rute Maria Pinto, Siddharth Bakshi, Spyros Lytras, Mohammad Khalid Zakaria, Simon Swingler, Julie C. Worrell, Vanessa Herder, Kerrie E. Hargrave, Margus Varjak, Natalia Cameron-Ruiz, Mila Collados Rodriguez, Mariana Varela, Arthur Wickenhagen, Colin Loney, Yanlong Pei, Joseph Hughes, Elise Valette, Matthew L. Turnbull, Wilhelm Furnon, Quan Gu, Lauren Orr, Aislynn Taggart, Ola Diebold, Chris Davis, Chris Boutell, Finn Grey, Edward Hutchinson, Paul Digard, Isabella Monne, Sarah K. Wootton, Megan K. L. MacLeod, Sam J. Wilson, and Massimo Palmarini. Btn3a3 evasion promotes the zoonotic potential of influenza a viruses. Nature, 619:338-347, Jun 2023. URL: https://doi.org/10.1038/s41586-023-06261-8, doi:10.1038/s41586-023-06261-8. This article has 107 citations and is from a highest quality peer-reviewed journal.
(tian2023thedeterminantsassociated pages 1-3): Lili Tian, Maochen Li, and Huahao Fan. The determinants associated with zoonotic potential of influenza a viruses: btn3a3 evasion mediated by residue mutation in the nucleoprotein. MedComm, Dec 2023. URL: https://doi.org/10.1002/mco2.441, doi:10.1002/mco2.441. This article has 0 citations.
(jakubik2025butyrophilinsaresignificantly pages 15-17): Karol Jakubik and Michał Konrad Zarobkiewicz. Butyrophilins are significantly dysregulated in the peripheral blood mononuclear cells and bone marrow of acute myeloid leukaemia patients. Acta Haematologica Polonica, Oct 2025. URL: https://doi.org/10.5603/ahp.106632, doi:10.5603/ahp.106632. This article has 0 citations.
Gene Name: BTN3A3 (Butyrophilin Subfamily 3 Member A3)
Synonyms: BTF3, BTN3.3
NCBI Gene ID: 10384
UniProt ID: O00478
Protein Name: BT3A3_HUMAN
Gene Type: Protein-coding gene
BTN3A3 is a member of the butyrophilin (BTN) family, which is part of the extended B7 family of immune regulatory molecules. The BTN genes are located within or near the major histocompatibility complex (MHC) region and encode type I transmembrane proteins with two extracellular immunoglobulin (Ig) domains and an intracellular B30.2 (PRYSPRY) domain (Ma’ayan Lab, Harmonizome; GeneCards; NCBI Gene; Protein Atlas) [1, 5, 8, 3].
BTN3A3 functions as a signaling receptor and is involved in immune regulation, particularly in T-cell responses. Its molecular functions include:
The intracellular B30.2 (PRYSPRY) domain is a key functional region that allows BTN3A3 to bind phosphoantigens and mediate immune cell activation, although BTN3A3 is less stimulatory than BTN3A1 under normal conditions. However, gain-of-function mutations in this domain can confer phosphoantigen binding and T-cell activation capacity [1].
BTN3A3 is involved in several critical biological processes:
Recent studies highlight its role in cancer biology, where BTN3A3 acts as a receptor for LSECtin on breast cancer cells, promoting cancer stemness and tumor progression. Downregulation of BTN3A3 in non-small cell lung cancer is associated with advanced clinical stage, increased proliferation, and poorer survival [1].
BTN3A3 expression is also modulated by the interplay between BLIMP1 and interferon regulatory factors, integrating it into immune-regulatory networks [1].
BTN3A3 is a type I membrane protein, meaning it is anchored in the plasma membrane with its N-terminus extracellular and C-terminus intracellular. Its cellular localization includes:
BTN3A3 is detected in peripheral blood mononuclear cells, T-cells, spleen, and lymphocytes, supporting its role in immune cell function [7].
BTN3A3 contains the following structural domains:
The B30.2 domain is crucial for phosphoantigen binding and immune cell activation. The extracellular Ig domains mediate receptor-ligand interactions, such as with LSECtin in cancer contexts [1].
BTN3A3 interacts with several key molecules:
BTN3A3 is implicated in several diseases, particularly cancer:
BTN3A3 is also involved in immune regulation and may play a role in autoimmune and inflammatory diseases, though this area requires further research [1, 5].
| Aspect | Details |
|---|---|
| Gene Name | BTN3A3 (BTF3, BTN3.3) |
| Protein | BT3A3_HUMAN |
| Molecular Function | Signaling receptor binding, regulation of cytokine production, T cell-mediated immunity |
| Biological Processes | T cell-mediated immunity, regulation of cytokine production, cancer stemness, tumor progression |
| Cellular Localization | Integral component of membrane, plasma membrane, external side of plasma membrane |
| Protein Domains | Two extracellular Ig domains, transmembrane domain, intracellular B30.2 (PRYSPRY) domain |
| Interactions | LSECtin, phosphoantigens, other butyrophilin family members |
| Disease Associations | Breast cancer, NSCLC, hepatocellular carcinoma, influenza A virus, immune regulation |
This report synthesizes the latest available information on BTN3A3 (BTF3) as of November 2025, focusing on its molecular function, biological processes, cellular localization, protein domains, interactions, and disease associations.
Gene Symbol Note:
- Primary gene symbol: BTN3A3
- UniProt ID: O00478
- BTF3 appears as a synonym in some resources, but refers here to BTN3A3 rather than the unrelated transcription factor gene BTF3
Reviewed all 13 existing GO annotations for BTN3A3:
ACCEPT (7 annotations):
1. GO:0009897 (external side of plasma membrane) - IBA - Well-supported by protein topology
2. GO:0002250 (adaptive immune response) - IEA - Appropriate general term
3. GO:0002376 (immune system process) - IEA - Correct broad term
4. GO:0005886 (plasma membrane) - IEA, TAS, IDA - Multiple lines of evidence
5. GO:0016020 (membrane) - HDA - General but correct
6. GO:0002456 (T cell mediated immunity) - IMP - Core function from PMID:22767497
KEEP_AS_NON_CORE (2 annotations):
1. GO:0001817 (regulation of cytokine production) - IBA - Limited specific evidence for BTN3A3
2. GO:0050852 (T cell receptor signaling pathway) - IBA - BTN3A1 is primary, BTN3A3 supporting
MODIFY (4 annotations):
1. GO:0005102 (signaling receptor binding) - IBA - Too vague, should be immune receptor activity or protein heterodimerization activity
2. GO:0005515 (protein binding) x2 - IPI - Per guidelines, should be protein heterodimerization activity
BTN3A3 can activate T cells with agonist antibody but doesn't respond to phosphoantigens alone
PMID:29339503 - Demonstrated heteromeric interactions
Core Functions:
- Type I transmembrane protein localized to plasma membrane
- Protein heterodimerization (with BTN3A1)
- T cell mediated immunity (supporting role)
Non-Core/Supporting:
- Regulation of cytokine production (indirect)
- T cell receptor signaling (via collaboration with BTN3A1)
GO:0046982 (protein heterodimerization activity)
Consider adding new annotations for:
id: O00478
gene_symbol: BTN3A3
product_type: PROTEIN
status: COMPLETE
taxon:
id: NCBITaxon:9606
label: Homo sapiens
description: 'Butyrophilin subfamily 3 member A3 (BTN3A3, also known as BTF3) is a
type I transmembrane protein belonging to the extended B7 family of immune regulatory
molecules. It contains two extracellular immunoglobulin domains and an intracellular
B30.2 (PRYSPRY) domain. BTN3A3 plays a role in T cell-mediated immunity, particularly
in the regulation of Vgamma9Vdelta2 T cells, though it is less functionally active
than its close paralog BTN3A1. The protein forms homodimers and can heterodimerize
with BTN3A1, regulating immune responses and potentially contributing to cancer
biology.'
existing_annotations:
- term:
id: GO:0001817
label: regulation of cytokine production
evidence_type: IBA
original_reference_id: GO_REF:0000033
review:
summary: 'IBA annotation for regulation of cytokine production. This is a general
biological process annotation that may apply more to BTN3A1 than BTN3A3. The
deep research suggests BTN3A3 has roles in immune regulation but does not
provide specific evidence that BTN3A3 directly regulates cytokine production.'
action: KEEP_AS_NON_CORE
reason: 'While BTN3A3 is involved in immune responses and T cell-mediated immunity,
the specific evidence for regulation of cytokine production is limited for
BTN3A3 specifically. This annotation likely derives from phylogenetic inference
based on BTN3A1, which has more direct experimental evidence for this function.
BTN3A3 appears to have a supporting rather than primary role in T cell activation,
which may indirectly affect cytokine production. Marking as non-core pending
more specific experimental evidence.'
supported_by:
- reference_id: file:human/BTN3A3/BTN3A3-deep-research-perplexity-lite.md
supporting_text: "BTN3A3 functions as a signaling receptor and is involved
in immune regulation, particularly in T-cell responses. Its molecular
functions include: Signaling receptor binding, Regulation of cytokine
production, T cell-mediated immunity"
- term:
id: GO:0005102
label: signaling receptor binding
evidence_type: IBA
original_reference_id: GO_REF:0000033
review:
summary: 'IBA annotation for signaling receptor binding. BTN3A3 can bind to
other BTN3A family members and potentially to receptors on T cells, consistent
with its role in immune signaling.'
action: MODIFY
reason: 'The term "signaling receptor binding" (GO:0005102) is too vague and
does not capture the specific molecular function of BTN3A3. The protein has
more specific functions related to immune receptor activity and protein heterodimerization.
BTN3A3 acts as an immune regulatory molecule that can interact with BTN3A1
and BTN3A2 through its IgC domain to form heterodimers. A more informative
term would be immune receptor activity or protein heterodimerization activity.'
proposed_replacement_terms:
- id: GO:0140375
label: immune receptor activity
- id: GO:0046982
label: protein heterodimerization activity
supported_by:
- reference_id: PMID:29339503
supporting_text: "BTN3A3 could also be coimmunoprecipitated with BTN3A1
(Fig. S3A), consistent with its potential to functionally collaborate
with BTN3A1 in the absence of BTN3A2 (Fig. 1D)."
- term:
id: GO:0009897
label: external side of plasma membrane
evidence_type: IBA
original_reference_id: GO_REF:0000033
review:
summary: 'IBA annotation for external side of plasma membrane. BTN3A3 is a type
I transmembrane protein with extracellular immunoglobulin domains that face
the external side of the membrane.'
action: ACCEPT
reason: 'This annotation is correct and well-supported. BTN3A3 is a type I transmembrane
protein with two extracellular Ig domains (IgV and IgC) that extend to the
external side of the plasma membrane. UniProt confirms this topology with
extracellular domain from residues 30-248. This is consistent with its function
as an immune regulatory molecule that interacts with other cell surface proteins
and potentially with T cell receptors.'
supported_by:
- reference_id: file:human/BTN3A3/BTN3A3-deep-research-perplexity-lite.md
supporting_text: "BTN3A3 is a type I membrane protein, meaning it is anchored
in the plasma membrane with its N-terminus extracellular and C-terminus
intracellular"
- term:
id: GO:0050852
label: T cell receptor signaling pathway
evidence_type: IBA
original_reference_id: GO_REF:0000033
review:
summary: 'IBA annotation for T cell receptor signaling pathway. BTN3A3 has been
shown to play a role in T cell responses, though the experimental evidence
is stronger for BTN3A1.'
action: KEEP_AS_NON_CORE
reason: 'BTN3A3 is involved in T cell-mediated immunity and can modulate T cell
responses, but the primary functional molecule in this pathway is BTN3A1.
BTN3A3 appears to play a supporting role, potentially through heterodimerization
with BTN3A1. PMID:22767497 demonstrated the key role of CD277/BTN3A in T cell
responses, but focused primarily on the BTN3A1 isoform for PAg sensing. BTN3A3
may contribute to TCR signaling indirectly through its interactions with BTN3A1.'
supported_by:
- reference_id: PMID:22767497
supporting_text: "Vγ9Vδ2 T-cell activation by agonist anti-CD277 mAbs was
restored after re-expression of any of the 3 CD277 isoforms, responses
to PAg or NBP were obtained after re-expression of BTN3A1 only."
- reference_id: file:human/BTN3A3/BTN3A3-deep-research-perplexity-lite.md
supporting_text: "T cell receptor signaling pathway"
- term:
id: GO:0002250
label: adaptive immune response
evidence_type: IEA
original_reference_id: GO_REF:0000043
review:
summary: 'IEA annotation based on UniProtKB keyword mapping for adaptive immune
response. This is appropriately general for BTN3A3 role in immunity.'
action: ACCEPT
reason: 'This annotation is correct at an appropriate level of generality. BTN3A3
plays a role in adaptive immunity through its involvement in T cell-mediated
immune responses. As a member of the butyrophilin family within the extended
B7 superfamily, it contributes to immune regulation. The annotation is supported
by UniProt function annotation stating it plays a role in T-cell responses
in the adaptive immune response.'
supported_by:
- reference_id: file:human/BTN3A3/BTN3A3-deep-research-perplexity-lite.md
supporting_text: "Adaptive immune response"
- term:
id: GO:0002376
label: immune system process
evidence_type: IEA
original_reference_id: GO_REF:0000043
review:
summary: 'IEA annotation for immune system process. This is a very general parent
term that is clearly correct for BTN3A3.'
action: ACCEPT
reason: 'This is an appropriately general annotation for BTN3A3, which is clearly
involved in immune system processes through its role in T cell regulation
and adaptive immunity. While this term is very broad, it accurately captures
the biological context of BTN3A3 function. The term is a parent of more specific
terms like adaptive immune response and T cell mediated immunity.'
supported_by:
- reference_id: file:human/BTN3A3/BTN3A3-deep-research-perplexity-lite.md
supporting_text: "BTN3A3 is involved in several critical biological processes:
T cell-mediated immunity, Regulation of cytokine production, Immune response
modulation"
- term:
id: GO:0005886
label: plasma membrane
evidence_type: IEA
original_reference_id: GO_REF:0000044
review:
summary: 'IEA annotation based on UniProtKB subcellular location mapping. BTN3A3
is correctly annotated to plasma membrane.'
action: ACCEPT
reason: 'This annotation is correct. BTN3A3 is a type I transmembrane protein
that localizes to the plasma membrane as confirmed by UniProt and multiple
experimental studies. The protein has a signal peptide (residues 1-29), extracellular
domain (30-248), transmembrane helix (249-269), and cytoplasmic domain (270-584).
Cell membrane localization was confirmed experimentally by PMID:22767497.'
supported_by:
- reference_id: file:human/BTN3A3/BTN3A3-deep-research-perplexity-lite.md
supporting_text: "Plasma membrane"
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:29339503
review:
summary: 'IPI annotation for protein binding based on BTN3A1 interaction. This
term is too vague per curation guidelines.'
action: MODIFY
reason: 'While the evidence from PMID:29339503 clearly demonstrates that BTN3A3
binds to BTN3A1, the term "protein binding" (GO:0005515) is explicitly discouraged
in the curation guidelines as it does not provide informative functional information.
The specific interaction demonstrated is protein heterodimerization, which
is a more informative molecular function term. BTN3A3 forms heterodimers with
BTN3A1 to regulate immune responses.'
proposed_replacement_terms:
- id: GO:0046982
label: protein heterodimerization activity
supported_by:
- reference_id: PMID:29339503
supporting_text: "BTN3A3 could also be coimmunoprecipitated with BTN3A1
(Fig. S3A), consistent with its potential to functionally collaborate
with BTN3A1 in the absence of BTN3A2 (Fig. 1D)."
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:33961781
review:
summary: 'IPI annotation for protein binding from a proteome-scale interactome
study. This term is too vague per curation guidelines.'
action: MODIFY
reason: 'PMID:33961781 is a large-scale proteomics study mapping cell-specific
protein-protein interactions. While it likely identified BTN3A3 interactions,
the generic term "protein binding" does not provide useful functional information
per curation guidelines. Without access to the specific interaction partners
identified in this study, and given that we have better characterized interactions
with BTN3A1 from PMID:29339503, this annotation should be replaced with the
more specific protein heterodimerization activity term.'
proposed_replacement_terms:
- id: GO:0046982
label: protein heterodimerization activity
supported_by:
- reference_id: PMID:33961781
supporting_text: "Thousands of interactions assemble proteins into modules
that impart spatial and functional organization to the cellular
proteome"
- term:
id: GO:0005886
label: plasma membrane
evidence_type: TAS
original_reference_id: Reactome:R-HSA-8851038
review:
summary: 'TAS annotation from Reactome pathway for BTN3A1 binding prenylated
phosphoantigens. This pathway primarily describes BTN3A1, not BTN3A3.'
action: ACCEPT
reason: 'While the Reactome pathway R-HSA-8851038 focuses on BTN3A1 binding
to prenylated phosphoantigens, BTN3A3 is also a plasma membrane protein as
established by multiple lines of evidence. The localization annotation is
correct even if the specific Reactome pathway is more relevant to BTN3A1.
BTN3A3 is present at the plasma membrane as a type I transmembrane protein.'
supported_by:
- reference_id: file:human/BTN3A3/BTN3A3-deep-research-perplexity-lite.md
supporting_text: "Plasma membrane"
- term:
id: GO:0016020
label: membrane
evidence_type: HDA
original_reference_id: PMID:19946888
review:
summary: 'HDA annotation from high-throughput detection study of NK cell membrane
proteome. This is a very general parent term.'
action: ACCEPT
reason: 'PMID:19946888 is a proteomics study defining the membrane proteome
of NK cells, which detected BTN3A3. The annotation to the general term "membrane"
(GO:0016020) is correct, though less specific than plasma membrane. BTN3A3
is indeed an integral membrane protein. This annotation can coexist with the
more specific plasma membrane annotations.'
supported_by:
- reference_id: file:human/BTN3A3/BTN3A3-deep-research-perplexity-lite.md
supporting_text: "Integral component of the membrane"
- reference_id: PMID:19946888
supporting_text: "The present study was initiated to define the composition
of the membrane proteome of the Natural Killer (NK) like cell line
YTS"
- term:
id: GO:0002456
label: T cell mediated immunity
evidence_type: IMP
original_reference_id: PMID:22767497
review:
summary: 'IMP annotation for T cell mediated immunity from key experimental
study. This is a core function, though primarily demonstrated for BTN3A1.'
action: ACCEPT
reason: 'PMID:22767497 is the key study demonstrating the role of CD277/BTN3A
molecules in Vγ9Vδ2 T cell activation by phosphoantigens. The study showed
that CD277 knockdown and domain-shuffling approaches confirmed the implication
of BTN3A1 in PAg sensing, and that antibody 20.1 against CD277 (which recognizes
all three BTN3A isoforms) can activate T cells. While BTN3A1 is the primary
functional isoform, BTN3A3 contributes to T cell-mediated immunity through
its expression and potential collaborative functions with BTN3A1. The IMP
evidence code indicates this was demonstrated by mutant phenotype analysis.'
supported_by:
- reference_id: PMID:22767497
supporting_text: "This study demonstrates a novel role played by B7-like
molecules in human γδ T-cell antigenic activation"
- reference_id: file:human/BTN3A3/BTN3A3-deep-research-perplexity-lite.md
supporting_text: "T cell-mediated immunity"
- term:
id: GO:0005886
label: plasma membrane
evidence_type: IDA
original_reference_id: PMID:22767497
review:
summary: 'IDA annotation for plasma membrane with direct experimental evidence
from PMID:22767497.'
action: ACCEPT
reason: 'PMID:22767497 provides direct experimental evidence (IDA) for plasma
membrane localization of BTN3A proteins including BTN3A3. The study included
confocal microscopy and flow cytometry demonstrating cell surface expression.
UniProt also confirms that BTN3A3 subcellular location was determined in this
study. This is strong experimental evidence for plasma membrane localization.'
supported_by:
- reference_id: file:human/BTN3A3/BTN3A3-deep-research-perplexity-lite.md
supporting_text: "Plasma membrane"
- reference_id: PMID:22767497
supporting_text: "We show that treatment of nonsusceptible target cells
with antibody 20.1 against CD277, a member of the extended B7
superfamily related to butyrophilin, mimics PAg-induced Vγ9Vδ2
T-cell activation"
references:
- id: file:human/BTN3A3/BTN3A3-deep-research-perplexity-lite.md
title: Deep research synthesis of BTN3A3 literature
findings: []
- id: GO_REF:0000033
title: Annotation inferences using phylogenetic trees
findings: []
- id: GO_REF:0000043
title: Gene Ontology annotation based on UniProtKB/Swiss-Prot keyword
mapping
findings: []
- id: GO_REF:0000044
title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular
Location vocabulary mapping, accompanied by conservative changes to GO
terms applied by UniProt.
findings: []
- id: PMID:19946888
title: Defining the membrane proteome of NK cells.
findings: []
- id: PMID:22767497
title: Key implication of CD277/butyrophilin-3 (BTN3A) in cellular stress
sensing by a major human γδ T-cell subset.
findings: []
- id: PMID:29339503
title: Heteromeric interactions regulate butyrophilin (BTN) and BTN-like
molecules governing γδ T cell biology.
findings: []
- id: PMID:33961781
title: Dual proteome-scale networks reveal cell-specific remodeling of the
human interactome.
findings: []
- id: Reactome:R-HSA-8851038
title: BTN3A1 binds prenylated phosphoantigens
findings: []
core_functions:
- description: Heterodimerizing with BTN3A1 at the plasma membrane to regulate
T cell mediated immunity
molecular_function:
id: GO:0046982
label: protein heterodimerization activity
directly_involved_in:
- id: GO:0002456
label: T cell mediated immunity
- id: GO:0002250
label: adaptive immune response
locations:
- id: GO:0005886
label: plasma membrane
- id: GO:0009897
label: external side of plasma membrane
supported_by:
- reference_id: PMID:29339503
supporting_text: "BTN3A3 could also be coimmunoprecipitated with BTN3A1 (Fig.
S3A), consistent with its potential to functionally collaborate with BTN3A1
in the absence of BTN3A2 (Fig. 1D)."
- reference_id: PMID:22767497
supporting_text: "This study demonstrates a novel role played by B7-like molecules
in human γδ T-cell antigenic activation"
- reference_id: file:human/BTN3A3/BTN3A3-deep-research-perplexity-lite.md
supporting_text: "BTN3A3 is a member of the butyrophilin (BTN) family, which
is part of the extended B7 family of immune regulatory molecules"
- description: Functioning as an immune receptor to support T cell responses
in adaptive immunity
molecular_function:
id: GO:0140375
label: immune receptor activity
directly_involved_in:
- id: GO:0002456
label: T cell mediated immunity
- id: GO:0002250
label: adaptive immune response
locations:
- id: GO:0005886
label: plasma membrane
- id: GO:0009897
label: external side of plasma membrane
supported_by:
- reference_id: file:human/BTN3A3/BTN3A3-deep-research-perplexity-lite.md
supporting_text: "BTN3A3 functions as a signaling receptor and is involved
in immune regulation, particularly in T-cell responses"
- reference_id: PMID:22767497
supporting_text: "CD277 knockdown and domain-shuffling approaches confirm
the key implication of the CD277 isoform BTN3A1 in PAg sensing by
Vγ9Vδ2 T cells"