Affinage

Showing FCGR3A — CD16 is a alias.

FCGR3A

Low affinity immunoglobulin gamma Fc region receptor III-A · UniProt P08637

Length
254 aa
Mass
29.1 kDa
Annotated
2026-06-09
100 papers in source corpus 28 papers cited in narrative 28 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

FCGR3A encodes CD16a/FcγRIIIa, a low-affinity activating IgG Fc receptor on NK cells, monocytes, and macrophages that recognizes antibody-coated targets to drive antibody-dependent cellular cytotoxicity (ADCC) and cytokine production (PMID:9276722, PMID:15817676, PMID:27906829). IgG-binding strength is set by multiple converging determinants: a coding V158F (also reported as residue 176) polymorphism in extracellular domain 2 confers higher IgG1/IgG3 binding, stronger calcium flux, and greater NK activation in V/V donors (PMID:9276722), while a single residue, Gly-129, accounts for the >10-fold higher affinity of CD16a over CD16b (PMID:30361439). Receptor affinity is further tuned by glycosylation on both partners: the composition of the CD16a Asn162 N-glycan dictates binding, with oligomannose structures—characteristic of NK cell-expressed but not recombinant receptor—increasing affinity ~12-fold (PMID:29330305, PMID:36189205), and core fucosylation of IgG1 Fc reduces affinity by ~1.7 kcal/mol by restricting the conformation of the CD16a Asn162-glycan (PMID:30016589). Lacking an intrinsic basic transmembrane residue, CD16a assembles with the ITAM-bearing FcεR1γ/CD247 adaptor complex through a network of polar and aromatic TM residues (F202, D205, T206) (PMID:28652325), and engagement triggers Syk, PI3K, and ERK signaling within lipid rafts, with PI3K-dependent activation of Arf6, PI5KIα, and PLD controlling lytic granule secretion required for ADCC (PMID:18174382, PMID:15817676). A unique cytoplasmic RSSTR motif is phosphorylated by PKC—antagonized by the binding partner S100A4—to bias signaling output between cytokine production and degranulation (PMID:23024279). Upon activation, CD16a is rapidly shed by ADAM17, limiting antibody tethering and effector function; a noncleavable engineered variant resists cleavage and enhances ADCC in vivo (PMID:15030579, PMID:30786043, PMID:31856277). In humanized mouse dengue models, CD16a engagement on splenic macrophages is the exclusive mediator of antibody-driven inflammatory pathogenesis (PMID:37429907).

Mechanistic history

Synthesis pass · year-by-year structured walk · 26 steps
  1. 1997 High

    Established that a coding polymorphism in CD16a extracellular domain 2 functionally tunes IgG binding and downstream NK activation, defining the receptor as a heritable determinant of antibody-driven effector strength.

    Evidence Flow cytometry IgG binding, calcium flux, and NK activation/apoptosis assays on genotyped V/V versus F/F donors

    PMID:9276722

    Open questions at the time
    • Did not resolve the structural basis of the affinity difference
    • Did not address glycan contributions to binding
  2. 2004 Medium

    Answered whether CD16a surface levels are dynamically regulated, showing metalloprotease-mediated shedding controls receptor occupancy and NK killing.

    Evidence MMP inhibitor effects on IgG binding, Lyn phosphorylation, and K562 cytotoxicity in primary NK cells

    PMID:15030579

    Open questions at the time
    • Specific protease not identified (pan-MMP inhibitor used)
    • Cleavage site not mapped
  3. 2005 High

    Defined the proximal signaling module linking CD16a engagement to lytic granule secretion via a small-GTPase cascade.

    Evidence PI3K inhibition, dominant-negative Arf6, co-IP, and ADCC assays in primary NK cells

    PMID:15817676

    Open questions at the time
    • Did not place Arf6/PLD relative to ITAM/Syk events
    • GEF activating Arf6 downstream of PI3K not identified
  4. 2007 High

    Quantified CD16a–IgG binding kinetics across IgG subtypes, providing the baseline affinity framework for the receptor.

    Evidence SPR, real-time flow cytometry, and competition inhibition with soluble CD16a-Fc fusion

    PMID:17202140

    Open questions at the time
    • Used recombinant receptor lacking native glycosylation
    • Did not address polymorphism or glycan effects
  5. 2008 High

    Showed CD16a signaling is spatially organized in lipid rafts and integrates with cytokine receptor signaling to amplify IFN-γ output.

    Evidence Confocal microscopy, fractionation, PI3K/ERK inhibitors, and dominant-negative ERK1 in primary NK cells

    PMID:18174382

    Open questions at the time
    • Mechanism of raft recruitment unresolved
    • Did not link to granule versus cytokine output choice
  6. 2009 Medium

    Demonstrated that FCGR3A copy number variation directly scales receptor surface expression, adding gene dosage to the determinants of CD16a function.

    Evidence MLPA CNV genotyping correlated with NK cell flow cytometry across individuals

    PMID:19309690

    Open questions at the time
    • Did not test functional ADCC consequences of CNV
    • Population frequency and disease links not established
  7. 2011 High

    Revealed that the expression system dictates CD16a Asn162 glycan structure and thereby IgG binding, foreshadowing the importance of native glycosylation.

    Evidence Glycopeptide mass spectrometry and SPR comparing HEK- versus CHO-derived receptor

    PMID:21561106

    Open questions at the time
    • Did not analyze primary cell-derived receptor
    • Did not isolate which glycan species drive binding
  8. 2012 High

    Identified a CD16a-unique cytoplasmic PKC-phosphorylation motif and a regulatory partner that bias signaling between cytokine production and degranulation.

    Evidence In vitro PKC phosphorylation, yeast two-hybrid (S100A4), mutagenesis, and calcium/Syk/cytokine/degranulation assays

    PMID:23024279

    Open questions at the time
    • Physiological trigger of PKC at this motif not defined
    • S100A4 regulation not validated in vivo at the cellular level
  9. 2012 Medium

    Linked monocyte CD16a expression to immune-complex-driven TNF production, extending the receptor's effector role beyond NK cells to inflammatory disease.

    Evidence Flow cytometry and intracellular TNF staining after heat-aggregated Ig stimulation in rheumatoid arthritis monocytes

    PMID:22235253

    Open questions at the time
    • Correlative, not causal for disease
    • Signaling pathway in monocytes not dissected
  10. 2015 Medium

    Mapped the CD16a-induced transcriptional program and connected it to in vivo antibody-mediated transplant rejection.

    Evidence Transcript profiling of CD16a-stimulated NK cells validated in kidney transplant biopsy microarrays

    PMID:27906829

    Open questions at the time
    • Biopsy association is correlative
    • Did not establish CD16a signaling causality in rejection
  11. 2015 Medium

    Established that CD16a can function as an inhibitory receptor through ITAMi/SHP-1 inhibisomes, revealing context-dependent dampening of heterologous activating receptors.

    Evidence IgG1/IVIg stimulation, SHP-1 recruitment, and inhibisome imaging (review summarizing experimental work)

    PMID:24728843

    Open questions at the time
    • Review-level synthesis rather than single primary dataset
    • Switch between ITAM and ITAMi states not mechanistically defined
  12. 2015 Medium

    Demonstrated CD16a acts as a CD28-independent co-stimulatory receptor on CD4+ T cells, driving pathogenic cytokine programs relevant to autoimmunity.

    Evidence IC stimulation, Syk phosphorylation, and IFN-γ/IL-17 assays in primary and SLE patient CD4+ T cells

    PMID:25556651 PMID:26582197

    Open questions at the time
    • Identity and origin of the CD16a+ T cell subset not fully defined
    • Causal role in human disease not proven
  13. 2017 High

    Resolved how CD16a, lacking a basic TM residue, assembles with FcεR1γ/CD247 adaptors and identified the residues forming the membrane-embedded interface.

    Evidence Extensive TM site-directed mutagenesis, molecular modeling, and surface expression/co-IP assays

    PMID:28652325

    Open questions at the time
    • No high-resolution structure of the assembled TM complex
    • Stoichiometry in native membranes not directly measured
  14. 2017 High

    Defined which of CD16a's five N-glycans contact the polypeptide, establishing a structural basis for glycan-dependent modulation of receptor conformation.

    Evidence 13C-labeled N-glycan HSQC NMR and 1 μs all-atom MD simulation

    PMID:28613884

    Open questions at the time
    • Did not quantify functional binding consequences of each contact
    • Glycan heterogeneity in vivo not captured
  15. 2018 High

    Provided the structural mechanism by which IgG Fc fucosylation lowers CD16a affinity, overturning the prior glycan-glycan contact model.

    Evidence Solution NMR, spin relaxation, and thermodynamic binding with truncated and intact Asn162 glycoforms

    PMID:30016589

    Open questions at the time
    • Effect measured on isolated Fc rather than full antibody-receptor synapse
    • Cellular consequence not directly tested here
  16. 2018 High

    Showed that native NK cell CD16a carries hybrid/oligomannose glycans that strongly elevate IgG binding, distinguishing physiological from recombinant receptor.

    Evidence Glycoproteomics of NK cell-derived CD16a, NMR, and IgG1 Fc binding affinity

    PMID:29330305

    Open questions at the time
    • Did not define the biosynthetic basis for the unusual glycans
    • Donor-to-donor variability not yet mapped
  17. 2018 High

    Pinpointed Gly-129 as the single residue conferring CD16a's high affinity over CD16b and providing glycan sensitivity, with crystallographic confirmation.

    Evidence Mutagenesis, binding affinity, 2.2 Å crystal structure of CD16b–IgG1 Fc, and 250-ns MD

    PMID:30361439

    Open questions at the time
    • No crystal structure of native glycosylated CD16a with oligomannose
    • Did not address cellular signaling consequences
  18. 2019 Medium

    Identified ADAM17 as the protease executing rapid activation-induced CD16a shedding and showed cleavage limits effector function, including in the tumor microenvironment.

    Evidence CD16a point mutation, ADAM17 inhibition, and ADCC/cytokine assays (review summarizing primary studies)

    PMID:30786043

    Open questions at the time
    • Review-level synthesis
    • Regulation of ADAM17 activation timing not defined
  19. 2019 High

    Demonstrated that primary NK cells preferentially retain proinflammatory afucosylated IgG1 and carry donor-variable oligomannose Asn162 glycans linked to high-affinity binding.

    Evidence Glycoproteomics and mass spectrometry of NK cell-bound IgG1 and CD16a from apheresis-derived cells

    PMID:31467031

    Open questions at the time
    • Mechanism driving selective afucosylated IgG retention unclear
    • Functional outcome of donor glycan variation not tested in vivo
  20. 2020 Medium

    Explained the cell-lineage basis of CD16a glycan composition by correlating glycan-modifying gene expression with receptor glycoforms.

    Evidence Glycoproteomics with RNA-Seq/qRT-PCR across NK cell lines and HEK293F

    PMID:33310702

    Open questions at the time
    • Correlative gene-expression link not validated by genetic perturbation here
    • Did not extend to primary tissue heterogeneity
  21. 2020 Medium

    Linked an immunodeficiency-associated allotype (H48) to altered N45 glycan processing, connecting glycosylation differences to receptor variants in primary cells.

    Evidence Glycoproteomics of CD16a from L48/H48 heterozygous donor NK cells and monocytes

    PMID:31967297

    Open questions at the time
    • Functional binding/signaling consequence of the N45 glycan difference not quantified
    • Disease causality not established
  22. 2020 High

    Provided proof-of-concept that a noncleavable high-affinity CD16a variant in iPSC-derived NK cells enhances antitumor ADCC in vivo, translating shedding biology into therapy.

    Evidence iPSC engineering with CD16a point mutation; in vitro ADCC and B-cell lymphoma xenograft models

    PMID:31856277

    Open questions at the time
    • Long-term in vivo persistence/safety not addressed
    • Generalizability across tumor types limited
  23. 2022 High

    Confirmed by genetic engineering that oligomannose Asn162 on CD16a plus afucosylated IgG1 jointly maximize binding affinity.

    Evidence CRISPR engineering of N-glycosylation pathways and binding assays with defined glycoforms

    PMID:36189205

    Open questions at the time
    • Did not test functional ADCC consequences of engineered glycoforms
    • In vivo relevance not assessed
  24. 2022 Medium

    Identified CD16a-unique residue Y140 enabling selective targeting by bispecific innate cell engagers, informing therapeutic specificity.

    Evidence Structural analysis and selectivity binding assays of a BCMA/CD16A bispecific

    PMID:35001074

    Open questions at the time
    • Structural detail from a single engineered complex
    • Role of Y140 in natural IgG engagement not addressed
  25. 2023 High

    Established CD16a on splenic macrophages as the exclusive mediator of antibody-driven dengue pathogenesis, defining an in vivo disease-specific effector role.

    Evidence Humanized FcγR mouse dengue models with FcγR-specific knockout and pathogenesis readouts

    PMID:37429907

    Open questions at the time
    • Downstream macrophage signaling pathway not dissected here
    • Human in vivo confirmation lacking
  26. 2025 High

    Showed that the L48 allotype variants enhance ADCC through faster killing kinetics, more compact synapses, and stronger calcium signaling independent of binding affinity, decoupling effector strength from IgG affinity.

    Evidence Primary NK and NK-92 ADCC, live-cell synapse imaging, calcium flux, and vesicle polarization assays

    PMID:39666369

    Open questions at the time
    • Molecular basis of affinity-independent signaling difference not resolved
    • In vivo therapeutic relevance not tested

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the distinct CD16a affinity determinants (V158F, Gly-129, Asn162 oligomannose, allotype-driven signaling, and IgG fucosylation) integrate quantitatively to set effector outcomes in vivo, and how ADAM17 shedding is temporally controlled during the killing cycle, remain unresolved.
  • No unified in vivo model linking each affinity determinant to effector output
  • Temporal regulation of ADAM17 shedding during serial killing undefined
  • Structure of the native glycosylated CD16a–adaptor signaling complex unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0038024 cargo receptor activity 3 GO:0060089 molecular transducer activity 3 GO:0001618 virus receptor activity 1 GO:0140110 transcription regulator activity 1
Localization
GO:0005886 plasma membrane 4
Pathway
R-HSA-162582 Signal Transduction 4 R-HSA-168256 Immune System 4
Partners
CD247FCER1GS100A4SYK
Complex memberships
CD16a–FcεR1γ/CD247 ITAM adaptor complex

Evidence

Reading pass · 28 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1997 A nonconservative T-to-G substitution at nucleotide 559 of FCGR3A predicts a phenylalanine (F) to valine (V) change at amino acid position 176 (also reported as position 158) in extracellular domain 2. NK cells and monocytes from V/V homozygotes bound more IgG1 and IgG3 than F/F homozygotes despite identical receptor expression levels, and V/V NK cells showed a larger calcium flux, greater NK cell activation, and more rapid activation-induced cell death upon aggregated IgG stimulus. Flow cytometry binding assays on genotyped homozygous donors; calcium flux measurement; functional NK cell activation and apoptosis assays The Journal of clinical investigation High 9276722
2007 Binding kinetics and equilibrium dissociation constants of FcγRIIIa (CD16a) to monomeric human IgG and subtypes IgG1, IgG3, and rabbit IgG were measured: on-rates ~6.5–18 × 10³ M⁻¹s⁻¹, off-rates ~4.7–19 × 10⁻³ s⁻¹, and Kd values of ~0.56–1.1 μM, using a soluble CD16a-Fc fusion protein. Results from surface plasmon resonance agreed with real-time flow cytometry and competition inhibition assays on cell-surface CD16a. Surface plasmon resonance (SPR); real-time flow cytometry; competition inhibition binding assays The Journal of biological chemistry High 17202140
2008 FcγRIIIa and the IL-12 receptor co-localize to lipid raft microdomains in NK cells upon co-stimulation with IgG and IL-12, leading to synergistic activation of Syk, PI3K, and ERK, and enhanced IFN-γ production. Chemical disruption of lipid rafts inhibited ERK signaling and IFN-γ production. ERK activation downstream of FcγRIIIa required sequential activation of Syk then PI3K. Confocal microscopy; cellular fractionation; specific chemical inhibitors of PI3K and ERK; retroviral transfection of dominant-negative and WT ERK1 into primary NK cells Blood High 18174382
2005 FcγRIIIa (CD16) stimulation on primary human NK cells induces PI3K-dependent activation of the small G protein Arf6, which in turn activates PI5KIα and phospholipase D (PLD). Arf6 (but not RhoA or Rac1) is required for receptor-induced PI5KIα membrane targeting and for PI5KIα and PLD activation, and Arf6-dependent signals control secretion of lytic granule content required for ADCC. Primary human NK cell stimulation assays; PI3K inhibition; dominant-negative Arf6; co-immunoprecipitation; functional ADCC cytotoxicity assay Blood High 15817676
2012 The unique cytoplasmic domain (CY) of FcγRIIIa (CD16A) contains an RSSTR motif specifically phosphorylated by PKC (not present in other Fcγ receptors). Phosphorylated CD16A mediates stronger calcium flux, Syk tyrosine phosphorylation, and proinflammatory cytokine production, whereas non-phosphorylatable CD16A favors Gab2/PI3K pathway activation and enhanced degranulation. S100A4 was identified as a new binding partner for CD16A-CY via yeast two-hybrid; S100A4 inhibits PKC-mediated phosphorylation of CD16A-CY in vitro, and reducing S100A4 in vivo enhances receptor phosphorylation upon crosslinking. In silico identification of PKC motif; in vitro PKC phosphorylation assay; yeast two-hybrid binding screen; site-directed mutagenesis; calcium flux, Syk phosphorylation, and cytokine/degranulation assays in NK cells Journal of immunology High 23024279
2017 CD16A association with signaling adaptor molecules FcεR1γ and CD247 (rather than depending on a basic residue in the TM domain as in other activating receptors) is mediated by a network of polar and aromatic residues along the TM domain length. Site-directed mutagenesis identified F202, D205, and T206 as forming the core of the membrane-embedded trimeric interface. D205 also regulates CD16A turnover and surface expression in the absence of FcεR1γ or CD247. Extensive site-directed mutagenesis of the CD16A TM domain; molecular modeling; surface expression and co-immunoprecipitation assays Proceedings of the National Academy of Sciences of the United States of America High 28652325
2018 Core fucosylation of IgG1 Fc reduces CD16a binding affinity by 1.7 ± 0.1 kcal/mol compared to afucosylated IgG1 Fc. This penalty is largely (1.2 ± 0.1 kcal/mol) reversed by truncating the CD16a N-glycan at Asn162. Fucosylation restricts the conformational ensemble of the CD16a Asn162-glycan—displacing it from the α-mannose(1-6)β-mannose linkage and promoting contact with IgG Tyr296—rather than acting through direct glycan-glycan contacts as previously proposed. Solution NMR spectroscopy; nuclear spin relaxation measurements; thermodynamic binding measurements ACS chemical biology High 30016589
2018 CD16a purified from primary human NK cells bears a large proportion of hybrid (22%) and oligomannose (23%) N-glycans—unlike recombinant CD16a which has predominantly complex-type N-glycans (82%). CD16a with oligomannose N-glycans bound IgG1 Fc with 12-fold greater affinity than CD16a with complex-type/highly branched N-glycans. Changes in binding activity mirrored changes in NMR spectra, indicating that N-glycan composition also affects CD16a structure. Glycoproteomics of NK cell-derived CD16a; NMR spectroscopy; IgG1 Fc binding affinity measurements The Journal of biological chemistry High 29330305
2017 Solution NMR profiling of the five N-glycans on CD16A identified that the N45 and N162 N-glycans make contacts with CD16A polypeptide residues (their anomeric resonances are dispersed from the rapidly averaged peaks of N38, N74, and N169 glycans), with computational simulations confirming unexpected contacts between the N45 glycan and CD16A polypeptide. 2D heteronuclear single-quantum coherence NMR with 13C-labeled N-glycans; 1 μs all-atom molecular dynamics simulation Biochemistry High 28613884
2018 A single residue, Gly-129, accounts for the >10-fold higher IgG binding affinity of CD16a versus CD16b. The CD16b-D129G variant bound IgG1 Fc with 90-fold higher affinity than WT CD16b and 2-fold higher than WT CD16a. Conversely, CD16a-G129D had 128-fold decreased affinity. IgG1 Fc binding in CD16a (and CD16b-D129G) was sensitive to N-glycan composition (oligomannose increased affinity ~5.2-fold); this sensitivity was lost in CD16b and CD16a-G129D. Crystal structure of glycosylated CD16b bound to IgG1 Fc at 2.2 Å combined with 250-ns MD simulation showed the larger Asp-129 side chain deforms the Fc-binding surface. Site-directed mutagenesis; IgG1 Fc binding affinity measurements; 2.2 Å crystal structure; 250-ns all-atom molecular dynamics simulation The Journal of biological chemistry High 30361439
2011 Cell type-specific N-glycosylation of FcγRIIIa at Asn-162 differs between HEK and CHO expression systems: HEK-derived receptor carries mostly multifucosylated biantennary Asn162-glycans (some with terminal GalNAc); CHO-derived carries bi- and triantennary highly sialylated glycans. SPR analysis showed that these differences in Asn162 glycosylation influence FcγRIIIa binding to immunoglobulin. Mass spectrometry of glycopeptides (multienzyme digest); surface plasmon resonance Journal of proteome research High 21561106
2004 Matrix metalloproteinase (MMP) inhibitor RU36156 increased IgG binding to FcγRIIIa on NK cells by 53.8%, increased phosphorylation of Lyn tyrosine kinase after crosslinking of the mIgG-FcγRIIIa complex, but when FcγRIIIa was occupied by mIgG, the MMP inhibitor decreased NK cell killing of K562 targets (because protection of CD16 from proteolysis keeps the receptor occupied and blocks other killing interactions). This indicated that FcγRIIIa undergoes metalloprotease-mediated shedding from the NK cell surface. Flow cytometry binding assays; 125I-mIgG kinetics; Lyn phosphorylation assay; NK cytotoxicity assay with MMP inhibitor Scandinavian journal of immunology Medium 15030579
2019 CD16A on human NK cells undergoes rapid activation-induced proteolytic cleavage by ADAM17 (a disintegrin and metalloproteinase-17). This cleavage can be prevented by a point mutation in CD16A. Inhibiting ADAM17 or preventing CD16A cleavage strengthens antibody tethering, decreases tumor cell detachment, and enhances CD16A signaling and cytokine production. NK cells in the tumor microenvironment downregulate CD16A, which impairs their function. Point mutation of CD16A; ADAM17 inhibition experiments; functional ADCC assays; NK cell activation measurements Journal of leukocyte biology Medium 30786043
2020 A high-affinity noncleavable variant of CD16a (hnCD16) engineered into iPSCs generates NK cells (hnCD16-iNK) that are highly resistant to activation-induced cleavage of CD16a and exhibit enhanced ADCC against multiple tumor targets in vitro. In vivo xenograft models showed significantly improved regression of B-cell lymphoma with hnCD16-iNK + anti-CD20 mAb versus PB-NK cells + anti-CD20 mAb. iPSC engineering with CD16a point mutation; in vitro ADCC assays; in vivo xenograft tumor models Blood High 31856277
2015 CD16a stimulation of human NK cells induced increased expression of 276 transcripts including IFNG, TNF, CSF2, chemokines (CCL3, CCL4, XCL1), and NK cell effector function modulators (TNFRSF9, CRTAM, CD160). CD16a-inducible NK cell-selective transcripts CD160 and XCL1 were found associated with antibody-mediated kidney transplant rejection biopsies, providing direct evidence that NK cell CD16a is activated in rejection. In vitro CD16a stimulation of primary human NK cells with transcript profiling; expression validation in human kidney transplant biopsy microarrays Transplantation Medium 27906829
2015 FcγRIIIa (CD16A) interaction with uncomplexed IgG1/IVIg or bivalent anti-FcγRIII F(ab')2 dampens calcium responses, ROS production, endocytosis, and phagocytosis triggered by heterologous activating receptors. This inhibitory action requires the inhibitory configuration of the ITAM motif (ITAMi) within the FcR γ-chain associated with FcγRIIIA, enabling SHP-1 recruitment and formation of inhibisome clusters containing FcγRIIIA and the targeted activating receptor. Cell stimulation assays with IgG1/IVIg; SHP-1 recruitment measurements; inhibisome cluster imaging; ITAMi signaling analysis Journal of clinical immunology Medium 24728843
2015 FcγRIIIa (CD16a) ligation by immune complexes (ICs) on a subset of activated CD4+ T cells provides a co-stimulatory signal analogous to CD28, triggering IFN-γ production via ITAM-mediated intracellular signaling. IC ligation via FcγRIIIa phosphorylated Syk on CD4+ T cells. Flow cytometry detection of FcγRIIIa on CD4+ T cells; IC stimulation assays; IFN-γ production measurement; Syk phosphorylation assay The Journal of biological chemistry Medium 25556651
2015 FcγRIIIa-pSyk signaling in CD4+ T cells (activated by IC ligation in SLE patients) provides co-stimulatory signal without CD28, leading to development of pathogenic IL-17A+ and IFN-γhigh CD4+ T cells. FcγRIIIa-pSyk differentially upregulated IFN pathway genes and several toll-like receptor genes (vs CD28 co-signal); ICs co-localized with TLR pathway proteins. SLE patient CD4+ T cell stimulation with ICs; Syk phosphorylation assay; cytokine production measurement; TLR gene expression; confocal co-localization The Journal of biological chemistry Medium 26582197
2009 Copy number variation (CNV) of FCGR3A was identified using MLPA assay. A gene-dosage effect of FCGR3A copy number correlated with FcγRIIIa expression levels on NK cells, indicating that FCGR3A CNV directly modulates receptor surface expression and function. Multiplex Ligation-dependent Probe Amplification (MLPA) for CNV genotyping; flow cytometric measurement of NK cell surface expression Human mutation Medium 19309690
2022 Comprehensive genetic engineering of N-glycosylation in mammalian cell lines confirmed that afucosylated IgG1 has the highest binding affinity to oligomannose FcγRIIIa. The key N-glycan feature driving increased binding is oligomannose at Asn162 on FcγRIIIa—a glycan structure commonly found on Asn162 on NK cell-expressed (but not monocyte- or recombinantly-expressed) FcγRIIIa. CRISPR-based genetic engineering of N-glycosylation pathways in mammalian cells; binding affinity measurements with defined glycoforms of both IgG1 and FcγRIIIa Frontiers in immunology High 36189205
2019 Primary NK cells retain proinflammatory (afucosylated) IgG1 at the cell surface; analysis of NK cell-bound IgG1 revealed sharp decrease in antibody fucosylation (43.2%) versus serum from the same donors (89.7%). CD16a N162-glycans showed the largest donor-dependent differences, with one donor displaying only oligomannose-type N-glycans at N162 that correlate with high-affinity IgG1 Fc binding. Isolation of primary NK cells from apheresis filters; glycoproteomics of CD16a and bound IgG1; mass spectrometry Molecular & cellular proteomics High 31467031
2020 CD16a N-glycan processing in NK cell lines (NK92, YTS) and HEK293F cells differs substantially. Gene expression profiling by RNA-Seq and qRT-PCR revealed that expression levels of glycan-modifying genes correlated with CD16a glycan composition across cell types, explaining how cell lineage determines CD16a N-glycan composition. Glycoproteomics; RNA-Seq; qRT-PCR of glycan-modifying genes; comparison across NK cell lines and HEK293F cells The Journal of biological chemistry Medium 33310702
2020 The N45 glycan on CD16a shows allotype-specific differences: CD16a H48 variant (associated with immunodeficiency) displays a greater proportion of complex-type N45 glycans compared to the common L48 allotype which has predominantly hybrid N45-glycoforms. These processing differences were observed in primary NK cells and monocytes from heterozygous donors. Mass spectrometry glycoproteomics of CD16a isolated from primary NK cells and monocytes of L48/H48 heterozygous donors Glycobiology Medium 31967297
2023 In in vivo mouse models of dengue disease expressing human FcγRs, the pathogenic activity of anti-DENV antibodies is exclusively mediated through engagement of FcγRIIIa on splenic macrophages, resulting in inflammatory sequelae and mortality. Other FcγRs did not contribute to this pathogenic activity. In vivo mouse models humanized for FcγRs; genetic ablation/specific FcγR knockout approach; dengue pathogenesis readouts (inflammatory sequelae and mortality) Nature microbiology High 37429907
2022 Structural analysis of a BCMA/CD16A bispecific innate cell engager revealed that selective CD16A binding (over CD16B and other FcγRs) is mediated through interaction with a single residue, Y140, that is uniquely present in CD16A opposite the Fc binding site. Structural analysis of bispecific antibody-CD16A interaction; selectivity binding assays against CD16A versus other FcγRs Leukemia Medium 35001074
2025 The L48-H and L48-R CD16 variants (FcγRIIIa) significantly enhance NK cell-mediated ADCC responses. NK cells expressing CD16 48-H killed and disengaged from target cells faster than those expressing CD16 48-L, resulting in improved serial killing. CD16 48-H formed a more compact immunologic synapse, generated more robust intracellular calcium signaling, and caused quicker polarization of cytolytic vesicles, without increasing CD16–IgG binding affinity. Primary NK cell ADCC assays; NK-92 cell assays; live-cell imaging of immunologic synapse; calcium flux measurement; cytolytic vesicle polarization assay Cancer immunology research High 39666369
2018 CD16A activation on NK cells by tetravalent bispecific antibody AFM13 (CD30/CD16A) enhanced subsequent IL2- and IL15-driven NK cell proliferation through upregulation of CD25 (IL2Rα) and CD132 (γc), increasing sensitivity to low-dose IL2 or IL15. CD16A-experienced NK cells exhibited increased NKG2D-mediated cytotoxicity against tumor targets and more vigorous IFN-γ production upon restimulation. NK cell stimulation with AFM13; flow cytometric analysis of CD25/CD132 upregulation; cytotoxicity assays; IFN-γ production measurement Cancer immunology research Medium 29514797
2012 Increased FcγRIIIa/CD16 expression on CD14++ monocytes in rheumatoid arthritis correlated with HAG (heat-aggregated immunoglobulin, i.e., immune complex)-induced TNF production (p<0.001), demonstrating that FcγRIIIa on monocytes mediates TNF production in response to immune complex stimulation. Flow cytometry for FcγRIIIa/CD16 expression; intracellular TNF staining after HAG stimulation; correlation analysis PloS one Medium 22235253

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2002 Therapeutic activity of humanized anti-CD20 monoclonal antibody and polymorphism in IgG Fc receptor FcgammaRIIIa gene. Blood 1518 11806974
1997 A novel polymorphism of FcgammaRIIIa (CD16) alters receptor function and predisposes to autoimmune disease. The Journal of clinical investigation 572 9276722
2007 FCGR2A and FCGR3A polymorphisms associated with clinical outcome of epidermal growth factor receptor expressing metastatic colorectal cancer patients treated with single-agent cetuximab. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 384 17704420
2020 Pluripotent stem cell-derived NK cells with high-affinity noncleavable CD16a mediate improved antitumor activity. Blood 235 31856277
2005 Polymorphisms in FcgammaRIIIA (CD16) receptor expression are associated with clinical response to rituximab in Waldenström's macroglobulinemia. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 193 15659493
2006 FCGR3A gene polymorphisms may correlate with response to frontline R-CHOP therapy for diffuse large B-cell lymphoma. Blood 164 16609067
2015 The molecular landscape of antibody-mediated kidney transplant rejection: evidence for NK involvement through CD16a Fc receptors. American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons 136 25787894
2015 The IL-15-Based ALT-803 Complex Enhances FcγRIIIa-Triggered NK Cell Responses and In Vivo Clearance of B Cell Lymphomas. Clinical cancer research : an official journal of the American Association for Cancer Research 131 26423796
2009 Copy number variation at the FCGR locus includes FCGR3A, FCGR2C and FCGR3B but not FCGR2A and FCGR2B. Human mutation 131 19309690
2002 Genetic linkage and association of Fcgamma receptor IIIA (CD16A) on chromosome 1q23 with human systemic lupus erythematosus. Arthritis and rheumatism 119 12209518
2018 CD16A Activation of NK Cells Promotes NK Cell Proliferation and Memory-Like Cytotoxicity against Cancer Cells. Cancer immunology research 118 29514797
2015 AFM13: a first-in-class tetravalent bispecific anti-CD30/CD16A antibody for NK cell-mediated immunotherapy. Journal of hematology & oncology 94 26231785
2017 Association of Polymorphisms in FCGR2A and FCGR3A With Degree of Trastuzumab Benefit in the Adjuvant Treatment of ERBB2/HER2-Positive Breast Cancer: Analysis of the NSABP B-31 Trial. JAMA oncology 92 27812689
2019 Role of ADAM17 as a regulatory checkpoint of CD16A in NK cells and as a potential target for cancer immunotherapy. Journal of leukocyte biology 90 30786043
2017 Evidence for CD16a-Mediated NK Cell Stimulation in Antibody-Mediated Kidney Transplant Rejection. Transplantation 86 27906829
2008 FcgammaRIIIa polymorphisms and cetuximab induced cytotoxicity in squamous cell carcinoma of the head and neck. Cancer immunology, immunotherapy : CII 86 18979096
2023 Control of acute myeloid leukemia by a trifunctional NKp46-CD16a-NK cell engager targeting CD123. Nature biotechnology 83 36635380
2018 Antibody Fucosylation Lowers the FcγRIIIa/CD16a Affinity by Limiting the Conformations Sampled by the N162-Glycan. ACS chemical biology 81 30016589
2022 From CD16a Biology to Antibody-Dependent Cell-Mediated Cytotoxicity Improvement. Frontiers in immunology 74 35720368
2006 Polymorphism in IgG Fc receptor gene FCGR3A and response to infliximab in Crohn's disease: a subanalysis of the ACCENT I study. Pharmacogenetics and genomics 70 17108815
2010 Correlation of FCGR3A and EGFR germline polymorphisms with the efficacy of cetuximab in KRAS wild-type metastatic colorectal cancer. European journal of cancer (Oxford, England : 1990) 67 20418097
2008 Colocalization of the IL-12 receptor and FcgammaRIIIa to natural killer cell lipid rafts leads to activation of ERK and enhanced production of interferon-gamma. Blood 67 18174382
2018 Restricted processing of CD16a/Fc γ receptor IIIa N-glycans from primary human NK cells impacts structure and function. The Journal of biological chemistry 66 29330305
2015 NK Cell and Ig Interplay in Defense against Herpes Simplex Virus Type 1: Epistatic Interaction of CD16A and IgG1 Allotypes of Variable Affinities Modulates Antibody-Dependent Cellular Cytotoxicity and Susceptibility to Clinical Reactivation. Journal of immunology (Baltimore, Md. : 1950) 65 26179905
2011 Cell type-specific and site directed N-glycosylation pattern of FcγRIIIa. Journal of proteome research 60 21561106
2021 Preclinical evaluation of AFM24, a novel CD16A-specific innate immune cell engager targeting EGFR-positive tumors. mAbs 59 34325617
2004 FCGR3A and FCGR2A polymorphisms may not correlate with response to alemtuzumab in chronic lymphocytic leukemia. Blood 59 15217834
2013 Correlation of HER2, FCGR2A, and FCGR3A gene polymorphisms with trastuzumab related cardiac toxicity and efficacy in a subgroup of patients from UNICANCER-PACS 04 trial. Breast cancer research and treatment 57 23780683
2015 Assessment of the Influence of Inflammation and FCGR3A Genotype on Infliximab Pharmacokinetics and Time to Relapse in Patients with Crohn's Disease. Clinical pharmacokinetics 56 25516415
2016 Cytokine-Induced Memory-Like Differentiation Enhances Unlicensed Natural Killer Cell Antileukemia and FcγRIIIa-Triggered Responses. Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation 54 27894857
2007 Association between SLE nephritis and polymorphic variants of the CRP and FcgammaRIIIa genes. Rheumatology (Oxford, England) 54 17596285
2018 A comprehensive overview of FCGR3A gene variability by full-length gene sequencing including the identification of V158F polymorphism. Scientific reports 50 30374078
2012 FcγRIIIa expression on monocytes in rheumatoid arthritis: role in immune-complex stimulated TNF production and non-response to methotrexate therapy. PloS one 47 22235253
2006 Association of FCGR2A and FCGR2A-FCGR3A haplotypes with susceptibility to giant cell arteritis. Arthritis research & therapy 46 16846526
2010 Rituximab-induced late-onset neutropenia in newly diagnosed B-cell lymphoma correlates with Fc receptor FcγRIIIa 158(V/F) polymorphism. American journal of hematology 45 20730791
2007 Affinity and kinetic analysis of Fcgamma receptor IIIa (CD16a) binding to IgG ligands. The Journal of biological chemistry 45 17202140
2014 Association of FCGR3A and FCGR3B copy number variations with systemic lupus erythematosus and rheumatoid arthritis in Taiwanese patients. Arthritis & rheumatology (Hoboken, N.J.) 44 25154742
2023 Bispecific killer cell engager with high affinity and specificity toward CD16a on NK cells for cancer immunotherapy. Frontiers in immunology 43 36685519
2017 Transmembrane features governing Fc receptor CD16A assembly with CD16A signaling adaptor molecules. Proceedings of the National Academy of Sciences of the United States of America 43 28652325
2018 FCGR2A/FCGR3A Gene Polymorphisms and Clinical Variables as Predictors of Response to Tocilizumab and Rituximab in Patients With Rheumatoid Arthritis. Journal of clinical pharmacology 42 30457672
2017 Trispecific antibodies for CD16A-directed NK cell engagement and dual-targeting of tumor cells. Protein engineering, design & selection : PEDS 42 28981915
2008 Associations between FCGR3A polymorphisms and susceptibility to rheumatoid arthritis: a metaanalysis. The Journal of rheumatology 42 18843786
2005 Arf6: a new player in FcgammaRIIIA lymphocyte-mediated cytotoxicity. Blood 42 15817676
2006 Analysis of Fcgamma receptor haplotypes in rheumatoid arthritis: FCGR3A remains a major susceptibility gene at this locus, with an additional contribution from FCGR3B. Arthritis research & therapy 40 16356189
2012 Platelet-associated antibodies, cellular immunity and FCGR3a genotype influence the response to rituximab in immune thrombocytopenia. British journal of haematology 39 22775462
2011 Combined Fc-protein- and Fc-glyco-engineering of scFv-Fc fusion proteins synergistically enhances CD16a binding but does not further enhance NK-cell mediated ADCC. Journal of immunological methods 39 21855548
2017 Carbohydrate-Polypeptide Contacts in the Antibody Receptor CD16A Identified through Solution NMR Spectroscopy. Biochemistry 36 28613884
2007 Evaluating the role of the genetic variations of PTPN22, NFKB1, and FcGRIIIA genes in inflammatory bowel disease: a meta-analysis. Inflammatory bowel diseases 36 17600378
2022 Role of N-Glycosylation in FcγRIIIa interaction with IgG. Frontiers in immunology 35 36189205
2014 Functional FCGR3A 158 V/F and IL-6 -174 C/G polymorphisms predict response to biologic therapy in patients with rheumatoid arthritis: a meta-analysis. Rheumatology international 35 24728031
2022 A BCMA/CD16A bispecific innate cell engager for the treatment of multiple myeloma. Leukemia 32 35001074
2014 FCGR2A and FCGR3A polymorphisms and clinical outcome in metastatic colorectal cancer patients treated with first-line 5-fluorouracil/folinic acid and oxaliplatin +/- cetuximab. BMC cancer 31 24884501
2019 FCGR3A and FCGR2A Genotypes Differentially Impact Allograft Rejection and Patients' Survival After Lung Transplant. Frontiers in immunology 30 31249568
2019 Primary Human Natural Killer Cells Retain Proinflammatory IgG1 at the Cell Surface and Express CD16a Glycoforms with Donor-dependent Variability. Molecular & cellular proteomics : MCP 30 31467031
2018 A single amino acid distorts the Fc γ receptor IIIb/CD16b structure upon binding immunoglobulin G1 and reduces affinity relative to CD16a. The Journal of biological chemistry 29 30361439
2016 The FCGR3A polymorphism predicts the response to rituximab-based therapy in patients with non-Hodgkin lymphoma: a meta-analysis. Annals of hematology 29 27431582
2017 Engineered aglycosylated full-length IgG Fc variants exhibiting improved FcγRIIIa binding and tumor cell clearance. mAbs 28 29173039
2012 FCGR2A/CD32A and FCGR3A/CD16A variants and EULAR response to tumor necrosis factor-α blockers in psoriatic arthritis: a longitudinal study with 6 months of followup. The Journal of rheumatology 28 22467926
2023 Engaging natural killer cells for cancer therapy via NKG2D, CD16A and other receptors. mAbs 26 37165468
2010 Analysis of MIF, FCGR2A and FCGR3A gene polymorphisms with susceptibility to pulmonary tuberculosis in Moroccan population. Journal of genetics and genomics = Yi chuan xue bao 26 20439102
2009 FCGR2B gene polymorphism rather than FCGR2A, FCGR3A and FCGR3B is associated with anti-GBM disease in Chinese. Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association 26 19640933
2023 Human FcγRIIIa activation on splenic macrophages drives dengue pathogenesis in mice. Nature microbiology 25 37429907
2015 The influence of NK cell-mediated ADCC: Structure and expression of the CD16 molecule differ among FcγRIIIa-V158F genotypes in healthy Japanese subjects. Human immunology 25 26582002
2015 Induced expression of FcγRIIIa (CD16a) on CD4+ T cells triggers generation of IFN-γhigh subset. The Journal of biological chemistry 24 25556651
2017 Effect of Fcγ-receptor 3a (FCGR3A) gene polymorphisms on rituximab therapy in Hungarian patients with rheumatoid arthritis. RMD open 23 29177079
2011 Polymorphism of the FcγRIIIa gene and post-treatment apical periodontitis. Journal of endodontics 23 21924179
2004 Interaction of human immunoglobulin G with CD16 on natural killer cells: ligand clearance, FcgammaRIIIA turnover and effects of metalloproteinases on FcgammaRIIIA-mediated binding, signal transduction and killing. Scandinavian journal of immunology 22 15030579
2022 High-affinity FcγRIIIa genetic variants and potent NK cell-mediated antibody-dependent cellular cytotoxicity (ADCC) responses contributing to severe COVID-19. Genetics in medicine : official journal of the American College of Medical Genetics 21 35488894
2020 Fc γ receptor IIIa/CD16a processing correlates with the expression of glycan-related genes in human natural killer cells. The Journal of biological chemistry 21 33310702
2017 The influence of FCGR2A and FCGR3A polymorphisms on the survival of patients with recurrent or metastatic squamous cell head and neck cancer treated with cetuximab. The pharmacogenomics journal 21 28719596
2015 FCGR2A, FCGR3A, FCGR3B polymorphisms and susceptibility to rheumatoid arthritis: a meta-analysis. Clinical and experimental rheumatology 21 26314337
2012 The unique cytoplasmic domain of human FcγRIIIA regulates receptor-mediated function. Journal of immunology (Baltimore, Md. : 1950) 21 23024279
2011 Polymorphisms of CD16A and CD32 Fcγ receptors and circulating immune complexes in Ménière's disease: a case-control study. BMC medical genetics 21 21208440
2022 Integrative Pan-Cancer Analysis Confirmed that FCGR3A is a Candidate Biomarker Associated With Tumor Immunity. Frontiers in pharmacology 19 35668930
2017 FCGR2A and FCGR3A Genotypes Correlate with Farletuzumab Response in Patients with First-Relapsed Ovarian Cancer Exhibiting Low CA125. Cytogenetic and genome research 19 29041009
2012 ABCB1, FCGR2A, and FCGR3A polymorphisms in patients with HER2-positive metastatic breast cancer who were treated with first-line taxane plus trastuzumab chemotherapy. Oncology 19 22906996
2012 The role of the FcGRIIIa polymorphism in modifying the association between treatment and outcome in patients with rheumatoid arthritis treated with rituximab versus TNF-α antagonist therapies. Clinical and experimental rheumatology 19 23294992
2019 FcγRIIIa chromatography to enrich a-fucosylated glycoforms and assess the potency of glycoengineered therapeutic antibodies. Journal of chromatography. A 18 31597603
2009 Dissection of the FCGR3A association with RA: increased association in men and with autoantibody positive disease. Annals of the rheumatic diseases 18 19700393
2005 Flow cytometric assay for determination of FcgammaRIIIA-158 V/F polymorphism. Journal of immunological methods 18 16181633
2022 Non-targeted characterization of attributes affecting antibody-FcγRIIIa V158 (CD16a) binding via online affinity chromatography-mass spectrometry. mAbs 17 34978527
2021 Oligomannose N-Glycans 3D Architecture and Its Response to the FcγRIIIa Structural Landscape. The journal of physical chemistry. B 17 33661628
2022 Examination of IgG Fc Receptor CD16A and CD64 Expression by Canine Leukocytes and Their ADCC Activity in Engineered NK Cells. Frontiers in immunology 16 35281028
2015 FcγRIIIa-Syk Co-signal Modulates CD4+ T-cell Response and Up-regulates Toll-like Receptor (TLR) Expression. The Journal of biological chemistry 16 26582197
2014 Role of FcγRIIIA (CD16) in IVIg-mediated anti-inflammatory function. Journal of clinical immunology 16 24728843
2003 Increase of soluble FcgRIIIa derived from natural killer cells and macrophages in plasma from patients with rheumatoid arthritis. The Journal of rheumatology 16 12966590
2021 Influence of the FCGR2A rs1801274 and FCGR3A rs396991 Polymorphisms on Response to Abatacept in Patients with Rheumatoid Arthritis. Journal of personalized medicine 15 34207385
2020 Allotype-specific processing of the CD16a N45-glycan from primary human natural killer cells and monocytes. Glycobiology 15 31967297
2017 Enhanced FCGR2A and FCGR3A signaling by HIV viremic controller IgG. JCI insight 15 28239647
2016 Characterizing the effect of multiple Fc glycan attributes on the effector functions and FcγRIIIa receptor binding activity of an IgG1 antibody. Biotechnology progress 15 27160519
2016 Identification of high-affinity anti-CD16A allotype-independent human antibody domains. Experimental and molecular pathology 15 27712994
2013 FcγRIIa and FcγRIIIa polymorphisms in childhood primary immune thrombocytopenia: implications for disease pathogenesis and outcome. Blood coagulation & fibrinolysis : an international journal in haemostasis and thrombosis 15 23249566
2024 Current Developments in NK Cell Engagers for Cancer Immunotherapy: Focus on CD16A and NKp46. Immune network 14 39513028
2016 FCGR3A/2A polymorphisms and diffuse large B-cell lymphoma outcome treated with immunochemotherapy: a meta-analysis on 1134 patients from two prospective cohorts. Hematological oncology 14 27282998
2025 First-in-Human Phase I Study of a CD16A Bispecific Innate Cell Engager, AFM24, Targeting EGFR-Expressing Solid Tumors. Clinical cancer research : an official journal of the American Association for Cancer Research 13 39846810
2019 FcγRIIIa receptor polymorphism influences NK cell mediated ADCC activity against HIV. BMC infectious diseases 13 31842762
2014 FCGR3A 158V/F polymorphism and response to frontline R-CHOP therapy in diffuse large B-cell lymphoma. DNA and cell biology 13 25050883
2025 The FcγRIIIA (CD16) L48-H/R Polymorphism Enhances NK Cell-Mediated Antibody-Dependent Cellular Cytotoxicity by Promoting Serial Killing. Cancer immunology research 12 39666369
2023 Inebilizumab reduces neuromyelitis optica spectrum disorder risk independent of FCGR3A polymorphism. Annals of clinical and translational neurology 12 37804003
2022 THP-1 cells transduced with CD16A utilize Fcγ receptor I and III in the phagocytosis of IgG-sensitized human erythrocytes and platelets. PloS one 12 36516219

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