Affinage

CR2

Complement receptor type 2 · UniProt P20023

Length
1033 aa
Mass
112.9 kDa
Annotated
2026-06-09
100 papers in source corpus 39 papers cited in narrative 39 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

CR2 (CD21) is a B-lymphocyte multi-ligand complement receptor that links innate complement opsonization to adaptive humoral immunity by lowering the threshold for B cell activation (PMID:2473114, PMID:11239449). Its N-terminal SCR1-2 domains constitute the primary ligand-binding module, engaging C3d/iC3b complement fragments through a charge-dependent interface in the recess between SCR1 and SCR2 (PMID:9794388, PMID:11352728, PMID:20083651), while a complementary positively charged SCR1-2 surface binds the negatively charged Epstein-Barr virus glycoprotein gp350 (PMID:17925391, PMID:18786993); the same domains also bind DNA, including methylated DNA with high affinity (PMID:22885687). CR2 is the EBV receptor: it is sufficient to confer EBV binding and infection on heterologous cells, soluble CR2 neutralizes infection, and CRISPR deletion abolishes EBV type 2 entry into T cells (PMID:6087328, PMID:2473114, PMID:2154612, PMID:32238579). CR2 also possesses Factor I cofactor activity toward membrane iC3b, and binds CD23 through SCR1-2 and SCR5-8 epitopes, mediating B cell and stromal cell adhesion and modulating IgE production (PMID:2437238, PMID:1386409, PMID:7780154, PMID:16172256). Functionally, CR2 partitions into a coreceptor complex with CD19 and TAPA-1/CD81 in which CD19 serves as the signaling subunit; co-ligation of CR2-bound complement-tagged antigen with the BCR drives co-translocation into lipid rafts, prolongs BCR signaling, recruits PI3-kinase and tyrosine-phosphorylated nucleolin, and promotes germinal-center B cell survival via c-FLIP upregulation (PMID:7690834, PMID:11207269, PMID:11239449, PMID:16116172, PMID:19706534). CR2 is transcriptionally restricted to its expressing lineage by an intronic silencer requiring a CBF1/RBP-J (Notch) site, DNA methylation, and histone deacetylation (PMID:9570543, PMID:11312253, PMID:11312258), and its extracellular domain is shed by stimulus-induced proteolysis following BCR or P2X7R activation (PMID:12938215, PMID:16740600). The coreceptor outcome is species-dependent: co-engagement enhances B cell activation in mice but is inhibitory in primary human B cells despite enhancing Ca2+ flux (PMID:33868238).

Mechanistic history

Synthesis pass · year-by-year structured walk · 24 steps
  1. 1984 High

    Established the founding identity of CR2 by showing it is the cellular receptor for Epstein-Barr virus, defining how a complement receptor doubles as a viral entry portal.

    Evidence Anti-CR2 mAb blocking, receptor transfer to S. aureus particles, and radiolabeled EBV binding on human B lymphocytes

    PMID:6087328

    Open questions at the time
    • Did not resolve whether CR2 alone is sufficient or requires accessory molecules
    • Binding site on CR2 for EBV not mapped
  2. 1987 High

    Demonstrated CR2 acts as a complement regulatory protein with Factor I cofactor activity, placing it functionally alongside CR1.

    Evidence In vitro cofactor assay with purified CR2 and Factor I on iC3b-bearing erythrocytes with mAb inhibition

    PMID:2437238

    Open questions at the time
    • Physiologic significance of cofactor activity in vivo not established
    • Does not address signaling role
  3. 1988 Medium

    Resolved that CR2 carries separable binding sites for EBV and C3d, indicating multi-ligand recognition is built into distinct epitopes rather than a shared surface.

    Evidence Reciprocal mAb blocking and anti-idiotypic antibodies

    PMID:2842398

    Open questions at the time
    • Sites localized only to functional epitopes, not to specific domains/residues
    • Single lab
  4. 1989 High

    Proved CR2 alone is sufficient to transfer both complement-receptor and EBV-receptor function, settling whether accessory proteins are required for either activity.

    Evidence Stable cDNA transfection into CR2-negative L cells and K562 with rosette and EBV infection readouts

    PMID:2473114

    Open questions at the time
    • Heterologous cells may lack downstream signaling partners present in B cells
    • Does not address coreceptor amplification
  5. 1990 Medium

    Clarified that CR2 binding initiates productive EBV infection rather than only mediating attachment, and defined murine gene architecture relevant to ortholog studies.

    Evidence Soluble recombinant CR2 infection-inhibition assay; cDNA/genomic cloning of murine Cr2

    PMID:2139460 PMID:2154612

    Open questions at the time
    • Post-binding entry steps not defined
    • Single-method infection inhibition
  6. 1991 Medium

    Extended CR2 expression beyond B cells to a subset of T lymphocytes, raising the possibility of CR2 function in T cell biology.

    Evidence Immunofluorescence and immunoprecipitation of 145 kDa CR2 from purified peripheral T cells

    PMID:1703182

    Open questions at the time
    • Functional consequence in T cells not demonstrated at this stage
    • Single lab
  7. 1992 High

    Identified CD23 (FcεRII) as a CR2 ligand and linked CR2 engagement to IL-4-induced IgE production, connecting the receptor to allergic/antibody-class regulation.

    Evidence CD23-liposome binding, CD21 transfection into BHK-21, blocking antibodies, IgE production assay

    PMID:1386409

    Open questions at the time
    • Physiologic relevance of CD23-CR2 axis in vivo not established
  8. 1993 High

    Defined the molecular architecture and signaling division of labor of the CR2/CD19/TAPA-1 coreceptor complex, establishing CR2 as the ligand-sensing subunit and CD19 as the signal transducer that amplifies BCR signaling.

    Evidence Chimeric domain-swap constructs in Daudi cells with calcium, PI3-kinase, and aggregation readouts; synthesizing review

    PMID:7688513 PMID:7690834

    Open questions at the time
    • Exact stoichiometry of the complex not resolved
    • Quantitative contribution of CR2 to signal amplification not isolated
  9. 1994 Medium

    Showed CR2 ligation through the C3dg/EBV site augments antigen-receptor-driven B cell activation via a tyrosine-kinase-dependent, c-fos-selective pathway, linking ligand binding to defined transcriptional and adhesive responses.

    Evidence Bead-coated ligand stimulation of resting B cells with c-fos/c-myc mRNA quantitation, aggregation, kinase inhibitors

    PMID:7525704

    Open questions at the time
    • Intermediate signaling components between CR2 and c-fos not identified
    • Single lab
  10. 1995 Medium

    Mapped CD23 binding to two CR2 regions (SCR1-2 and SCR5-8) and connected CR2-CD23 interaction to cell adhesion, including myeloma-stroma interactions.

    Evidence Epitope mapping/mutagenesis of CD21 residues; antibody-blocking adhesion assays with myeloma and stromal cells

    PMID:7542093 PMID:7780154

    Open questions at the time
    • Methodological detail limited in epitope study
    • In vivo relevance of myeloma adhesion not tested
  11. 1998 High

    Localized the C3dg binding site to the SCR1-SCR2 junction recess and defined an intronic silencer governing lineage-restricted CR2 expression, addressing both ligand recognition and transcriptional control.

    Evidence Peptide epitope mapping with blocking mAb FE8 and homology modeling; reporter transfection and transgenic mice for silencer

    PMID:9570543 PMID:9794388

    Open questions at the time
    • Trans-acting factors binding the silencer not yet identified at this stage
    • Atomic-resolution structure of the binding interface not available
  12. 1999 Medium

    Demonstrated low-level epithelial CR2 supports EBV binding and infection independently of CD35 and CD19, showing CR2 functions as an autonomous entry receptor across cell types.

    Evidence Anti-CD21 blocking of EBV binding/infection in 293 cells lacking CD35/CD19

    PMID:9971794

    Open questions at the time
    • Efficiency relative to B cell infection not benchmarked
    • Single lab
  13. 2001 High

    Defined the biophysical and signaling basis of CR2 function: SCR1-2 as the primary charge-dependent C3d-binding module, distinct ligand kinetics, a CR2-specific nucleolin/PI3-kinase signaling branch, lipid-raft co-translocation prolonging BCR signaling, and CBF1/Notch- and epigenetically-controlled lineage-specific transcription.

    Evidence SPR/CD/ultracentrifugation on recombinant SCR constructs; mass-spec identification of phospho-nucleolin and SH2 binding; lipid raft fractionation with BCR kinetics; silencer mutagenesis/EMSA and methylation/HDAC pharmacology; crystal-structure-corroborated mAb mapping

    PMID:11207269 PMID:11239449 PMID:11312253 PMID:11312258 PMID:11352728 PMID:11466369 PMID:11698449 PMID:9144490

    Open questions at the time
    • Physiologic CR2-C3d interface later disputed
    • How nucleolin signaling integrates with CD19 amplification not resolved
    • Stoichiometry of raft co-translocation not quantified
  14. 2003 High

    Characterized stimulus-induced proteolytic shedding of the CR2 ectodomain from B cells, identifying a regulated mechanism that generates soluble CD21 and removes surface receptor after activation.

    Evidence Mass spectrometry and N-terminal sequencing of plasma sCD21; stimulation and B/T cell source determination

    PMID:12938215

    Open questions at the time
    • Responsible protease not identified
    • Functional role of soluble CD21 not established
  15. 2005 High

    Established a survival function for CR2 coreceptor signaling—c-FLIP upregulation protecting germinal-center B cells from CD95 apoptosis—and defined the molecular basis of the CD21-CD23 interaction structurally.

    Evidence Adoptive transfer of Cr2-/- Ig-transgenic B cells with Cr2 x lpr epistasis and c-FLIP/apoptosis assays; NMR structure of the CD23 C-type lectin domain

    PMID:16116172 PMID:16172256

    Open questions at the time
    • Signaling link between CR2/CD19 and c-FLIP transcription not fully mapped
    • Whether CD23-CR2 contributes to survival not tested
  16. 2007 High

    Defined the gp350 binding surface on CR2 SCR1-2 as a positively charged contiguous patch and demonstrated that stromal (not hematopoietic) CR2/35 on follicular dendritic cells mediates prion retention, expanding CR2's role to antigen/agent trapping.

    Evidence Systematic SCR1-2 mutagenesis with gp350 binding on K562; reciprocal bone marrow chimeras with prion challenge

    PMID:17925391 PMID:17947689

    Open questions at the time
    • Mechanism of FDC retention of prions at molecular level not defined
    • Whether DNA/complement binding contributes to prion trapping unknown
  17. 2008 High

    Resolved the complementary electrostatic chemistry of the CR2-gp350 interface, explaining how charge pairing dictates EBV receptor recognition.

    Evidence Mutagenesis of both gp350 and CR2 SCR1-2 with cell-surface binding and HADDOCK docking

    PMID:18786993

    Open questions at the time
    • No co-crystal structure of the CR2-gp350 complex
    • Affinity contribution of individual residues not ranked
  18. 2009 High

    Genetically uncoupled CR2 ligand binding from CD19 signaling, revealing a CD19-independent contribution of CR2 to B cell memory while confirming CD19 dependence for germinal-center survival and antibody titers.

    Evidence Knockin Cr2-GFP mice that bind C3 but cannot signal through CD19, with immunization and GC/antibody readouts versus complete KO

    PMID:19706534

    Open questions at the time
    • Molecular basis of the CD19-independent memory function not identified
    • Whether non-CD19 partners mediate this role unknown
  19. 2010 High

    Re-mapped the functional CR2-binding site on C3d to the concave-face acidic pocket, challenging the physiologic relevance of the previously reported cocrystal interface.

    Evidence SPR with a panel of C3dg variants against CR2 SCR1-2 and Sbi-IV

    PMID:20083651

    Open questions at the time
    • Discrepancy with crystallographic interface not fully reconciled
    • Conformational state of C3d governing binding not resolved
  20. 2012 High

    Identified DNA, especially methylated DNA, as a high-affinity CR2 ligand via SCR1-2, with in vivo immune defects to bacterial DNA, broadening CR2 ligand repertoire beyond complement and viral proteins.

    Evidence SPR with multiple DNA forms, truncated SCR constructs, blocking mAb, and immunization of Cr2-/- mice

    PMID:22885687

    Open questions at the time
    • Mechanism by which DNA binding shapes immune responses not defined
    • Relationship to complement/EBV binding sites not fully delineated
  21. 2018 Medium

    Showed CR2 physically associates with FCRL5 and converts it from a negative to a positive coreceptor, illustrating that CR2 can rewire the signaling output of partner receptors.

    Evidence Co-immunoprecipitation and calcium flux assays in cell lines and tonsil B cells with FCRL5 transfection

    PMID:30107486

    Open questions at the time
    • Reciprocal validation and stoichiometry of CR2-FCRL5 association limited
    • In vivo relevance not tested
    • Single lab
  22. 2019 Medium

    Linked upstream cytoskeletal regulator DOCK2 to CR2 expression via LEF1, connecting B cell developmental signaling to CR2/CD19 coreceptor abundance.

    Evidence Genetic mouse models (DOCK2-/-, LEF1-deficient) with expression and BCR signaling assays

    PMID:31405607

    Open questions at the time
    • Direct LEF1 action on CR2 locus not demonstrated
    • Single lab
  23. 2020 High

    Established CR2 as the required receptor for EBV type 2 entry into T cells, extending its viral-entry function to the T lineage.

    Evidence CRISPR knockout of CD21 in Jurkat cells, neutralizing antibodies, and primary T cell infection

    PMID:32238579

    Open questions at the time
    • Whether T cell entry uses the same gp350 interface as B cells not confirmed
    • Co-receptor requirements in T cells not defined
  24. 2021 Medium

    Revealed a species divergence in CR2 coreceptor function—co-engagement inhibits human B cell activation despite enhancing Ca2+ flux, contrasting with the positive role established in mice.

    Evidence Co-clustering of BCR and CR2 on primary human B cells with Ca2+, activation, cytokine, and antibody readouts

    PMID:33868238

    Open questions at the time
    • Molecular basis for the human-specific inhibitory outcome not defined
    • Single lab; contradicts mouse data

Open questions

Synthesis pass · forward-looking unresolved questions
  • How CR2's distinct ligand-binding activities (complement, EBV gp350, CD23, DNA) are integrated to set coreceptor signaling outcomes, and why those outcomes diverge between mouse and human B cells, remains unresolved.
  • No unified structural model reconciling the disputed C3d interface
  • Species-specific signaling mechanism unexplained
  • Protease responsible for ectodomain shedding unidentified

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0001618 virus receptor activity 5 GO:0060089 molecular transducer activity 3 GO:0098631 cell adhesion mediator activity 2 GO:0003677 DNA binding 1 GO:0098772 molecular function regulator activity 1
Localization
GO:0005886 plasma membrane 3
Pathway
R-HSA-162582 Signal Transduction 3 R-HSA-1643685 Disease 3 R-HSA-168256 Immune System 3
Partners
CD19CD23CD35CD81FCRL5
Complex memberships
CD21/CD19/TAPA-1 (CD81) coreceptor complex

Evidence

Reading pass · 39 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1984 CR2 (CD21) is the Epstein-Barr virus receptor on human B lymphocytes, established by showing that anti-CR2 monoclonal antibodies block EBV binding and that transfer of CR2 from B cells to Staphylococcus aureus particles confers specific EBV binding ability. Monoclonal antibody blocking assay, receptor transfer to heterologous particles, radiolabeled EBV binding assay Proceedings of the National Academy of Sciences of the United States of America High 6087328
1987 CR2 has cofactor activity for Factor I-mediated cleavage of membrane-bound iC3b, releasing C3c, demonstrating functional similarity to CR1 as a complement regulatory protein. In vitro cofactor activity assay with purified CR2 and Factor I on 125I-labeled iC3b-bearing erythrocytes; inhibition by anti-CR2 mAb OKB7 The Journal of experimental medicine High 2437238
1988 CR2 carries two distinct binding sites: one for EBV and one for C3d, demonstrated using anti-CR2 mAbs that selectively block one ligand but not the other, and anti-idiotypic antibodies that mimic extracellular domains of CR2. Monoclonal antibody blocking assays, anti-idiotypic antibody production, affinity chromatography Journal of immunology (Baltimore, Md. : 1950) Medium 2842398
1988 Aggregated and particulate CR2 ligands (C3dg, anti-CR2 mAb OKB7, UV-inactivated EBV) enhance B cell transition from G1 to S phase when combined with phorbol ester activation, while monomeric C3dg is inhibitory; signaling is T cell- and monocyte-independent. Thymidine incorporation assay, purified resting tonsil B cells, comparison of monomeric vs. aggregated/particulate ligands Journal of immunology (Baltimore, Md. : 1950) Medium 2459218
1989 CR2 cDNA transfection into CR2-negative mouse L cells and human K562 cells confers both C3bi/C3d binding (rosette formation) and EBV binding/infection, demonstrating CR2 alone is sufficient to transfer complement receptor and EBV receptor functions. Stable transfection, flow cytometry, rosette assay with complement-coated erythrocytes, EBV infection and EBNA expression Journal of immunology (Baltimore, Md. : 1950) High 2473114
1990 Soluble recombinant CR2 inhibits EBV infection of B cells in vitro, demonstrating that CR2 binding initiates EBV infection rather than merely mediating virus attachment. In vitro EBV infection inhibition assay with soluble recombinant CR2 Journal of virology Medium 2154612
1990 The murine Cr2 gene produces two proteins via alternative splicing: a larger ~190 kDa protein with CR1-like N-terminal domains and a smaller ~145 kDa protein homologous to human CR2, both sharing the same signal sequence. cDNA cloning, DNA sequence analysis, RNA protection studies, genomic phage mapping Journal of immunology (Baltimore, Md. : 1950) High 2139460
1991 CR2 (CD21) is expressed on 30-40% of normal human peripheral blood T lymphocytes at ~10-fold lower intensity than B cells, immunoprecipitated as a 145 kDa protein, suggesting CR2 may modulate T cell function. Indirect immunofluorescence with biotinylated anti-CR2 mAb, immunoprecipitation from purified T lymphocytes Journal of immunology (Baltimore, Md. : 1950) Medium 1703182
1992 CD21 (CR2) is a ligand for CD23 (FcεRII); fluorescent CD23-liposomes specifically bind CD21 on B cells and CD21-transfected BHK-21 cells, and triggering CD21 with anti-CD21 antibody or soluble CD23 specifically increases IL-4-induced IgE production. Fluorescent liposome binding assay, CD21 cDNA transfection into BHK-21 cells, anti-CD21/anti-CD23 blocking antibodies, Western blot, IgE production assay from blood mononuclear cells Nature High 1386409
1993 Within the CD21/CD19/TAPA-1 complex, CD19 and TAPA-1 interact through their extracellular domains, CD19 and CD21 interact through extracellular and transmembrane domains, and CD21 and CD35 interact through extracellular domains; CD21 is required for TAPA-1-dependent homotypic cellular aggregation but not for CD19-mediated PI3-kinase recruitment or calcium signaling. Chimeric molecule construction (HLA-A2/CD4 domain swaps), stable transfection in Daudi cells, functional assays for calcium flux, PI3-kinase association, homotypic aggregation The Journal of experimental medicine High 7690834
1993 CD21/CD19/TAPA-1 complex amplifies signaling through membrane immunoglobulin and recruits PI3-kinase; CD19 is the signaling subunit coupling to Lyn and PI3-kinase, while CR2 enables nonimmunologic ligation of CD19 via C3 fragments. Review synthesizing biochemical and genetic data (functional complex characterization) Current opinion in immunology Medium 7688513
1994 CD21 ligands binding to the C3dg/EBV-binding site of CR2 markedly augment B cell activation initiated by antigen receptor ligation via a tyrosine kinase-dependent, c-fos-selective pathway; beads coated with anti-CD21 mAb to the C3dg-binding portion trigger homotypic B cell aggregation. Latex bead coated with antibodies/ligands, c-fos and c-myc mRNA quantitation, homotypic aggregation assay, tyrosine kinase inhibitor studies with purified small resting B cells Journal of immunology (Baltimore, Md. : 1950) Medium 7525704
1995 CR2 binds CD23 at two main epitope regions: SCRs 1-2 and SCRs 5-8, with Asn370 and Asn295 in the SCR 5-8 region being critical for the interaction with the lectin CD23. Epitope mapping with anti-CD23 antibodies, mutagenesis of CD21 residues International archives of allergy and immunology Medium 7542093
1995 CD21 expressed on myeloma cells mediates adhesion to bone marrow stromal cells via CD23 on stromal cells; antibody blocking of either CD21 or CD23 inhibits this adhesion. Antibody-blocking adhesion assay, flow cytometry for CD21/CD23 expression, myeloma cell lines and primary stromal cells Blood Medium 7780154
1998 CR2 (CD21) gene expression is regulated by a B cell- and stage-specific intronic silencer: the 2.5-kb first intron segment silences promoter activity specifically in non-CR2-expressing cells, and this silencer requires nuclear matrix/chromatin interactions in stable (but not transient) transfection. Transient and stable transfection with reporter gene constructs, transgenic mice Journal of immunology (Baltimore, Md. : 1950) High 9570543
1998 C3dg binding to CR2 occurs in the recess formed between SCR1 and SCR2; a mAb (FE8) recognizing a discontinuous epitope spanning sequences at the SCR1-SCR2 junction blocks C3dg binding and EBV infection. Epitope mapping with overlapping peptides on cellulose, mAb inhibition of C3dg binding and EBV infection, 3D homology modeling Journal of immunology (Baltimore, Md. : 1950) Medium 9794388
1999 Low-level surface CD21 expression on epithelial 293 cells supports EBV binding and stable infection; both virus binding and infection are blocked by anti-CD21 antibodies, and CD35 and CD19 are not required. Anti-CD21 antibody blocking of EBV binding and infection, flow cytometry, EBV infection of 293 cells with selectable marker Journal of virology Medium 9971794
2001 CR2 binding to gp350 follows a simple 1:1 kinetics, whereas binding to C3d and iC3b is more complex and involves more than one intramolecular component; iC3b binds CR2 with different kinetics depending on whether it is soluble or surface-immobilized, suggesting an additional binding site in the C3c region of iC3b. Surface plasmon resonance (SPR) kinetic analysis of CR2 interactions with C3d, iC3b, and gp350/220 Journal of immunology (Baltimore, Md. : 1950) High 11466369
2001 The SCR 1-2 domains of CR2 account for the primary C3dg binding site; the additional SCR domains of full-length CR2 slow both the association and dissociation rates. The SCR1-2:C3d interaction forms a 1:1 complex and is influenced by ionic (charge-dependent) interactions, with the sole His residue near the SCR1-SCR2 linker potentially affecting ligand association. Recombinant CR2 SCR1-2 and SCR1-15 expression in Pichia pastoris/baculovirus, circular dichroism, surface plasmon resonance, sedimentation equilibrium ultracentrifugation, homology modeling Biochemistry High 11352728
2001 An inhibitory anti-CR2 mAb (171) directly contacts the C3d binding site on CR2 SCR1-2 as confirmed by placement of its linear epitope on the CR2-C3d crystal structure, providing solution-phase confirmation of the crystallographic binding interface. Anti-CR2 mAb generation in Cr2-/- mice, overlapping peptide epitope mapping, CR2-C3d crystal structure-based analysis, ligand binding inhibition assays Journal of immunology (Baltimore, Md. : 1950) High 11698449
2001 CD21 (CR2) activation on B lymphocyte surface triggers tyrosine phosphorylation of nucleolin (p95) and its interaction with PI3-kinase p85 subunit, SH2 domains of 3BP2 and Grb2 (but not Fyn or Gap), within 2 minutes; this signaling is specific to CR2 activation and not induced by CD19 or BCR activation. Anti-phosphotyrosine affinity purification, mass spectrometry amino acid analysis, anti-nucleolin antibody co-precipitation, SH2 domain binding assay Journal of immunology (Baltimore, Md. : 1950) High 11207269
2001 Binding of complement-tagged antigens causes co-translocation of both BCR and CD19/CD21 complex into plasma membrane lipid rafts, prolonging BCR residency and signaling in rafts compared to BCR cross-linking alone; CD19/CD21 co-ligation also retards BCR internalization and degradation. Lipid raft fractionation, co-localization assays, BCR internalization and degradation kinetics, complement-tagged antigen stimulation Immunity High 11239449
2001 A site within the CR2 intronic silencer contains a CBF1 (RBP-J/RBP-Jκ) binding site; a 2-bp mutation eliminating CBF1 binding abolishes silencer activity in vivo, demonstrating that CBF1 (a Notch signaling component) controls CR2 lineage-specific expression. Site-directed mutagenesis of silencer, stable transfection reporter assay, EMSA (in vitro binding) International immunology High 11312253
2001 Murine CD21 gene expression requires both promoter sequences and a 5'-proximal intronic element; the first intron contains an 800-bp 5' inhibitory element active in both B and T cells and an 800-bp 3' element that is inhibitory in T cells but acts as an enhancer in B cells. Transient transfection with luciferase reporter constructs, minigene analysis Journal of immunology (Baltimore, Md. : 1950) Medium 9144490
2001 CR2 (CD21) expression is regulated by DNA methylation of the CpG island near the ATG start codon and by histone deacetylation; 5-aza-2'-deoxycytidine (DNA methyltransferase inhibitor) and trichostatin A (histone deacetylase inhibitor) both induce CD21 expression in early B lymphocytes that normally lack it. Methylation analysis of CpG island in cell lines, 5-aza-2'-deoxycytidine treatment, trichostatin A treatment International immunology Medium 11312258
2003 Soluble CD21 (sCD21) shed into human plasma is predominantly a short form lacking exon-11-encoded sequences; shedding involves proteolytic cleavage of only the extracellular portion (C terminus truncated), is induced by PMA+calcium ionophore or BCR stimulation (anti-IgM+anti-CD40), and peripheral blood B cells (not T cells) are the primary source. Mass spectrometry of purified plasma sCD21, N-terminal sequencing, flow cytometry after stimulation, B/T cell separation experiments European journal of immunology High 12938215
2005 The NMR structure of the C-type lectin domain of CD23 identifies distinct binding sites for IgE and CD21; CD23 can bind both ligands simultaneously and does not require calcium for either interaction. IgE and CD23 can form high molecular mass multimeric complexes. NMR solution structure determination, concentration-dependent chemical shift perturbation analysis for binding site mapping, molecular weight analysis The Journal of experimental medicine High 16172256
2005 CD21/CD19 coreceptor signaling promotes B cell survival in primary immune responses via upregulation of c-FLIP, protecting against CD95-mediated apoptosis; Cr2-/- B cells show reduced c-FLIP levels and fail to persist in follicles, rescued by the lpr mutation. Adoptive transfer of Cr2-/- and Cr2+/+ Ig-transgenic B cells, c-FLIP mRNA and protein quantitation, in vitro HEL-C3d3 stimulation, CD95-mediated apoptosis assay Journal of immunology (Baltimore, Md. : 1950) High 16116172
2006 CD21 shedding is induced by P2X7 receptor activation (via BzATP, a P2X7R agonist) on peripheral B cells, in addition to BCR stimulation; P2X7R-mediated shedding was confirmed using receptor inhibitors. BzATP stimulation of peripheral blood lymphocytes, P2X7R inhibitor experiments, flow cytometry for surface CD21 International immunology Medium 16740600
2007 The gp350 binding site on CR2 involves a large contiguous surface on SCR1-2 dominated by positively charged residues (Arg-13, Arg-28, Arg-36, Lys-41, Lys-57, Lys-67, Arg-83, and within SCR2 via mAbs 171/1048); both SCR1 and SCR2 make contact with gp350. Site-directed mutagenesis of CR2 SCR1-2, expression on K562 cells, gp350 binding by flow cytometry, anti-CR2 mAb inhibition The Journal of biological chemistry High 17925391
2007 Stromal (not hematopoietic) CD21/35 on follicular dendritic cells is required for splenic retention of prion inocula and lymphoid prion colonization; bone marrow chimera experiments showed that protection from prion infection in CD21/35-/- mice is due to loss of stromal CD21/35. Reciprocal bone marrow adoptive transfer between WT and CD21/35-/- mice, prion challenge, infectivity titration in spleens Journal of immunology (Baltimore, Md. : 1950) High 17947689
2008 The CR2 binding site on EBV gp350 is defined by a negatively charged surface (Glu-21, Asp-22, Glu-155, Asp-208, Glu-210, Asp-296) and hydrophobic contacts (Tyr-151, Ile-160, Trp-162); the complementary positively charged residues on CR2 SCR1-2 (Arg-13, Arg-28, Arg-36, Lys-41, Lys-57, Lys-67, Arg-83, Arg-89) mediate the charge-dependent interaction. ELISA with recombinant wild-type and mutant gp350 and CR2 SCR1-2, K562 cell binding assay with PE-conjugated gp350, HADDOCK docking model Journal of virology High 18786993
2009 Uncoupling CD21 from CD19 (via knockin of mutant Cr2 that binds C3 but does not signal through CD19) significantly diminishes germinal center B cell survival and secondary antibody titers, but B memory is less impaired than in complete CR deficiency, identifying a CD19-independent role for CR in B cell memory. Knockin mice expressing Cr2-GFP fusion that binds C3 ligands but fails to signal through CD19, immunization, antibody titer measurement, GC B cell flow cytometry Proceedings of the National Academy of Sciences of the United States of America High 19706534
2010 The CR2-binding site on C3d maps to the concave face acidic pocket; mutations to concave face residues significantly impair both CR2 and Staphylococcal Sbi-IV binding, while mutations to the sideface region implicated by the cocrystal structure show no binding defects, casting doubt on the physiologic relevance of the CR2-C3d cocrystal interface. Surface plasmon resonance with panel of C3dg variant proteins against biosensor-bound CR2 SCR1-2 or Sbi-IV Journal of immunology (Baltimore, Md. : 1950) High 20083651
2012 CR2 binds multiple forms of DNA (bacterial, viral, mammalian) with moderately high affinity; methylated DNA binds with high affinity (Kd ~6 nM) via the first two SCR domains; binding is blocked by an inhibitory anti-CR2 mAb; Cr2-/- mice show specific immune response defects to bacterial DNA. Surface plasmon resonance, anti-CR2 mAb blocking, truncated SCR domain constructs, immunization of Cr2-/- mice Molecular immunology High 22885687
2019 DOCK2 deficiency reduces CD21 expression at both mRNA and protein levels through a mechanism involving upregulation of lymphoid enhancer-binding factor 1 (LEF1), leading to downregulation of CD19-mediated BCR signaling and reduced marginal zone B cells. Genetic models (DOCK2-/-, WASP-/-, LEF1-deficient mice), flow cytometry, mRNA/protein expression analysis, BCR signaling assays The Journal of allergy and clinical immunology Medium 31405607
2020 CD21 is required for EBV type 2 entry into T cells; viral gp350 and CD21 are both necessary for CD3+ T-cell infection, and CRISPR knockout of CD21 in Jurkat T cells abolishes EBV entry. Neutralizing antibody assay, CRISPR-Cas9 knockout of CD21 in Jurkat cells, flow cytometry for CD21 expression on T cell subsets, ex vivo infection model Journal of virology High 32238579
2021 Co-engagement of CR2 (CD21) and the BCR on primary human B cells inhibits activation marker expression, cytokine production, proliferation, and antibody production at non-stimulatory concentrations of anti-Ig, while enhancing Ca2+ response; this differs from the positive coreceptor role established in mice. Co-clustering of BCR and CR2 on primary human B cells, Ca2+ flux assay, activation marker expression by flow cytometry, cytokine/antibody production measurement Frontiers in immunology Medium 33868238
2018 CD21 and FCRL5 physically associate on B cells; triple engagement of FCRL5, CD21, and BCR produces superior calcium response compared to CD21+BCR co-stimulation alone; CD21 co-engagement converts FCRL5 from a negative to a positive co-receptor, recruiting CD19, active PLCγ2, and BTK to FCRL5. Co-immunoprecipitation, calcium flux assay in cell lines and tonsil B cells, FCRL5 transfection with/without CD21 International immunology Medium 30107486

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1984 Epstein-Barr virus receptor of human B lymphocytes is the C3d receptor CR2. Proceedings of the National Academy of Sciences of the United States of America 853 6087328
1992 CD21 is a ligand for CD23 and regulates IgE production. Nature 433 1386409
1995 The CD19/CR2/TAPA-1 complex of B lymphocytes: linking natural to acquired immunity. Annual review of immunology 396 7542009
2010 Complement receptor 2/CD21- human naive B cells contain mostly autoreactive unresponsive clones. Blood 384 20231422
2000 Regulation of B lymphocyte responses to foreign and self-antigens by the CD19/CD21 complex. Annual review of immunology 376 10837064
1985 Human follicular dendritic cells express CR1, CR2, and CR3 complement receptor antigens. Journal of immunology (Baltimore, Md. : 1950) 233 2411809
1994 The CD19/CD21 signal transduction complex of B lymphocytes. Immunology today 225 7524521
2017 Low CD21 expression defines a population of recent germinal center graduates primed for plasma cell differentiation. Science immunology 222 28783670
1991 Expression of CR2 (the C3dg/EBV receptor, CD21) on normal human peripheral blood T lymphocytes. Journal of immunology (Baltimore, Md. : 1950) 211 1703182
1993 Functional dissection of the CD21/CD19/TAPA-1/Leu-13 complex of B lymphocytes. The Journal of experimental medicine 196 7690834
2013 Expansion of autoreactive unresponsive CD21-/low B cells in Sjögren's syndrome-associated lymphoproliferation. Arthritis and rheumatism 193 23279883
2001 The CD19/CD21 complex functions to prolong B cell antigen receptor signaling from lipid rafts. Immunity 165 11239449
2007 Complement receptors CD21 and CD35 in humoral immunity. Immunological reviews 141 17850488
1990 The murine complement receptor gene family. IV. Alternative splicing of Cr2 gene transcripts predicts two distinct gene products that share homologous domains with both human CR2 and CR1. Journal of immunology (Baltimore, Md. : 1950) 139 2139460
2021 The expansion of human T-bethighCD21low B cells is T cell dependent. Science immunology 124 34623902
2004 Cutting edge: BAFF regulates CD21/35 and CD23 expression independent of its B cell survival function. Journal of immunology (Baltimore, Md. : 1950) 123 14707045
2005 The structure of human CD23 and its interactions with IgE and CD21. The Journal of experimental medicine 113 16172256
2009 Differential expression of CD21 identifies developmentally and functionally distinct subsets of human transitional B cells. Blood 110 19965666
1988 CR2 ligands modulate human B cell activation. Journal of immunology (Baltimore, Md. : 1950) 101 2459218
2016 CD21(-/low) B cells in human blood are memory cells. Clinical and experimental immunology 75 27010233
1993 The CD19-CR2-TAPA-1 complex, CD45 and signaling by the antigen receptor of B lymphocytes. Current opinion in immunology 75 7688513
2015 CD21 -/low B cells: A Snapshot of a Unique B Cell Subset in Health and Disease. Scandinavian journal of immunology 70 26119182
2022 Human T-bet governs the generation of a distinct subset of CD11chighCD21low B cells. Science immunology 69 35867801
2009 Expression and role of CR1 and CR2 on B and T lymphocytes under physiological and autoimmune conditions. Molecular immunology 68 19559484
2008 Comparative functional evolution of human and mouse CR1 and CR2. Journal of immunology (Baltimore, Md. : 1950) 68 18713965
1999 CD21-Dependent infection of an epithelial cell line, 293, by Epstein-Barr virus. Journal of virology 66 9971794
2001 Kinetic analysis of the interactions of complement receptor 2 (CR2, CD21) with its ligands C3d, iC3b, and the EBV glycoprotein gp350/220. Journal of immunology (Baltimore, Md. : 1950) 65 11466369
2001 CD19, CD21, and CD22: multifaceted response regulators of B lymphocyte signal transduction. International reviews of immunology 65 11913948
2007 High CD21 expression inhibits internalization of anti-CD19 antibodies and cytotoxicity of an anti-CD19-drug conjugate. British journal of haematology 58 17991300
2007 Stromal complement receptor CD21/35 facilitates lymphoid prion colonization and pathogenesis. Journal of immunology (Baltimore, Md. : 1950) 57 17947689
2002 A role for the Cr2 gene in modifying autoantibody production in systemic lupus erythematosus. Journal of immunology (Baltimore, Md. : 1950) 56 12133988
2017 Neonatal and adult recent thymic emigrants produce IL-8 and express complement receptors CR1 and CR2. JCI insight 55 28814669
2003 B cell activation leads to shedding of complement receptor type II (CR2/CD21). European journal of immunology 55 12938215
2013 Peripheral CD27-CD21- B-cells represent an exhausted lymphocyte population in hepatitis C cirrhosis. Clinical immunology (Orlando, Fla.) 53 24434272
1989 Analysis of epitope expression and the functional repertoire of recombinant complement receptor 2 (CR2/CD21) in mouse and human cells. Journal of immunology (Baltimore, Md. : 1950) 52 2473114
1994 Modulation of signaling via the B cell antigen receptor by CD21, the receptor for C3dg and EBV. Journal of immunology (Baltimore, Md. : 1950) 51 7525704
2013 CR2-mediated targeting of complement inhibitors: bench-to-bedside using a novel strategy for site-specific complement modulation. Advances in experimental medicine and biology 49 23402024
2011 CD23(+)/CD21(hi) B-cell translocation and ipsilateral lymph node collapse is associated with asymmetric arthritic flare in TNF-Tg mice. Arthritis research & therapy 48 21884592
2001 Structural studies in solution of the recombinant N-terminal pair of short consensus/complement repeat domains of complement receptor type 2 (CR2/CD21) and interactions with its ligand C3dg. Biochemistry 48 11352728
1998 CD21/CD35 in B cell activation. Seminars in immunology 47 9695184
1995 Regulation of IgE synthesis by CD23/CD21 interaction. International archives of allergy and immunology 47 7542093
2021 Revisiting the Coreceptor Function of Complement Receptor Type 2 (CR2, CD21); Coengagement With the B-Cell Receptor Inhibits the Activation, Proliferation, and Antibody Production of Human B Cells. Frontiers in immunology 46 33868238
2020 CD21 (Complement Receptor 2) Is the Receptor for Epstein-Barr Virus Entry into T Cells. Journal of virology 46 32238579
2019 CD21-/low B cells associate with joint damage in rheumatoid arthritis patients. Scandinavian journal of immunology 45 31141193
2005 The CD19-CD21 signal transduction complex of B lymphocytes regulates the balance between health and autoimmune disease: systemic sclerosis as a model system. Current directions in autoimmunity 45 15564717
1990 Soluble recombinant CR2 (CD21) inhibits Epstein-Barr virus infection. Journal of virology 44 2154612
2022 A close-up on the expanding landscape of CD21-/low B cells in humans. Clinical and experimental immunology 43 36380692
2008 Molecular basis of the interaction between complement receptor type 2 (CR2/CD21) and Epstein-Barr virus glycoprotein gp350. Journal of virology 43 18786993
1998 An intronic silencer regulates B lymphocyte cell- and stage-specific expression of the human complement receptor type 2 (CR2, CD21) gene. Journal of immunology (Baltimore, Md. : 1950) 42 9570543
1987 Functional and antigenic properties of complement receptor type 2, CR2. The Journal of experimental medicine 41 2437238
2021 New aspects in the regulation of human B cell functions by complement receptors CR1, CR2, CR3 and CR4. Immunology letters 40 34186155
2020 Naive- and Memory-like CD21low B Cell Subsets Share Core Phenotypic and Signaling Characteristics in Systemic Autoimmune Disorders. Journal of immunology (Baltimore, Md. : 1950) 40 32907998
2001 Epitope mapping using the X-ray crystallographic structure of complement receptor type 2 (CR2)/CD21: identification of a highly inhibitory monoclonal antibody that directly recognizes the CR2-C3d interface. Journal of immunology (Baltimore, Md. : 1950) 40 11698449
1992 Expression of the complement regulatory proteins CD21, CD55 and CD59 on Burkitt lymphoma lines: their role in sensitivity to human serum-mediated lysis. European journal of immunology 40 1378022
2020 The Antigen Presenting Potential of CD21low B Cells. Frontiers in immunology 39 33193306
1989 Murine complement receptor gene family. II. Identification and characterization of the murine homolog (Cr2) to human CR2 and its molecular linkage to Crry. Journal of immunology (Baltimore, Md. : 1950) 39 2528587
2005 CD21/CD19 coreceptor signaling promotes B cell survival during primary immune responses. Journal of immunology (Baltimore, Md. : 1950) 38 16116172
2012 Systemic human CR2-targeted complement alternative pathway inhibitor ameliorates mouse laser-induced choroidal neovascularization. Journal of ocular pharmacology and therapeutics : the official journal of the Association for Ocular Pharmacology and Therapeutics 37 22309197
1995 Expression of CD21 antigen on myeloma cells and its involvement in their adhesion to bone marrow stromal cells. Blood 37 7780154
1990 Comparative structure and evolution of murine CR2. The homolog of the human C3d/EBV receptor (CD21). Journal of immunology (Baltimore, Md. : 1950) 36 2139457
2017 High SYK Expression Drives Constitutive Activation of CD21low B Cells. Journal of immunology (Baltimore, Md. : 1950) 35 28468967
1998 Characterization of C3dg binding to a recess formed between short consensus repeats 1 and 2 of complement receptor type 2 (CR2; CD21). Journal of immunology (Baltimore, Md. : 1950) 35 9794388
1988 Monoclonal and anti-idiotypic anti-EBV/C3d receptor antibodies detect two binding sites, one for EBV and one for C3d on glycoprotein 140, the EBV/C3dR, expressed on human B lymphocytes. Journal of immunology (Baltimore, Md. : 1950) 34 2842398
2010 Mutational analyses reveal that the staphylococcal immune evasion molecule Sbi and complement receptor 2 (CR2) share overlapping contact residues on C3d: implications for the controversy regarding the CR2/C3d cocrystal structure. Journal of immunology (Baltimore, Md. : 1950) 33 20083651
2009 Uncoupling CD21 and CD19 of the B-cell coreceptor. Proceedings of the National Academy of Sciences of the United States of America 32 19706534
2004 Signaling by the CD19/CD21 complex on B cells. Current directions in autoimmunity 32 14719373
2000 Reduced expression of the complement receptor type 2 (CR2, CD21) by synovial fluid B and T lymphocytes. Clinical and experimental immunology 32 11091285
2021 T-bet+CD27+CD21- B cells poised for plasma cell differentiation during antibody-mediated rejection of kidney transplants. JCI insight 31 34032636
2020 CD21low B cells in systemic sclerosis: A possible marker of vascular complications. Clinical immunology (Orlando, Fla.) 31 32087329
2012 Oral dysplasia and squamous cell carcinoma: correlation between increased expression of CD21, Epstein-Barr virus and CK19. Oral oncology 31 22513207
2006 CD21 and CD62L shedding are both inducible via P2X7Rs. International immunology 31 16740600
2001 A site in the complement receptor 2 (CR2/CD21) silencer is necessary for lineage specific transcriptional regulation. International immunology 31 11312253
2001 Cell-specific regulation of the CD21 gene. International immunopharmacology 31 11367532
2023 T-bethighCD21low B cells: the need to unify our understanding of a distinct B cell population in health and disease. Current opinion in immunology 29 36931129
2018 CD21 and FCRL5 form a receptor complex with robust B-cell activating capacity. International immunology 29 30107486
2012 Human complement receptor 2 (CR2/CD21) as a receptor for DNA: implications for its roles in the immune response and the pathogenesis of systemic lupus erythematosus (SLE). Molecular immunology 29 22885687
1989 Epstein-Barr virus/complement fragment C3d receptor (CR2) reacts with p53, a cellular antioncogene-encoded membrane phosphoprotein: detection by polyclonal anti-idiotypic anti-CR2 antibodies. Proceedings of the National Academy of Sciences of the United States of America 29 2557614
2019 Dedicator of cytokinesis protein 2 couples with lymphoid enhancer-binding factor 1 to regulate expression of CD21 and B-cell differentiation. The Journal of allergy and clinical immunology 28 31405607
2016 The Structure-Function Relationships of Complement Receptor Type 2 (CR2; CD21). Current protein & peptide science 28 26916158
1995 Role of Epstein-Barr virus and soluble CD21 in persistent polyclonal B-cell lymphocytosis. British journal of haematology 28 7646990
1989 Variability of CR2 gene products is due to alternative exon usage and different CR2 alleles. Journal of immunology (Baltimore, Md. : 1950) 28 2565927
2021 CD27-CD38lowCD21low B-Cells Are Increased in Axial Spondyloarthritis. Frontiers in immunology 27 34168654
2007 Isolating the Epstein-Barr virus gp350/220 binding site on complement receptor type 2 (CR2/CD21). The Journal of biological chemistry 27 17925391
1990 Loss of human CR1- and murine Crry-like exons in human CR2 transcripts due to CR2 gene mutations. Journal of immunology (Baltimore, Md. : 1950) 27 2144008
2003 Decreased levels of serum soluble complement receptor-II (CR2/CD21) in patients with rheumatoid arthritis. Rheumatology (Oxford, England) 26 12867574
2003 Regulation of B-cell activation by complement receptors CD21 and CD35. Current pharmaceutical design 26 12871189
2000 Quantitative expression of CD23 and its ligand CD21 in chronic lymphocytic leukemia. Haematologica 26 11064465
1995 Expression of Epstein-Barr virus nuclear antigen-2 (EBNA2) induces CD21/CR2 on B and T cell lines and shedding of soluble CD21. European journal of immunology 26 7614999
2001 Regulation of CD21 expression by DNA methylation and histone deacetylation. International immunology 25 11312258
1997 Expression of the murine CD21 gene is regulated by promoter and intronic sequences. Journal of immunology (Baltimore, Md. : 1950) 25 9144490
1990 Deficiencies of human C3 complement receptors type 1 (CR1, CD35) and type 2 (CR2, CD21). Immunodeficiency reviews 25 2164822
2001 Activation of the EBV/C3d receptor (CR2, CD21) on human B lymphocyte surface triggers tyrosine phosphorylation of the 95-kDa nucleolin and its interaction with phosphatidylinositol 3 kinase. Journal of immunology (Baltimore, Md. : 1950) 24 11207269
2000 Regulation of humoral immune responses by CD21/CD35. Immunological reviews 24 11043778
1992 CD4-independent binding of HIV-1 to the B lymphocyte receptor CR2 (CD21) in the presence of complement and antibody. Clinical and experimental immunology 24 1360879
2022 Uncontrolled CD21low age-associated and B1 B cell accumulation caused by failure of an EGR2/3 tolerance checkpoint. Cell reports 23 35045301
1995 Mutation of residues in the C3dg region of human complement component C3 corresponding to a proposed binding site for complement receptor type 2 (CR2, CD21) does not abolish binding of iC3b or C3dg to CR2. Journal of immunology (Baltimore, Md. : 1950) 23 7868901
1993 Murine macrophages lack expression of the Cr2-145 (CR2) and Cr2-190 (CR1) gene products. European journal of immunology 22 7693486
2020 Phthalide derivative CD21 alleviates cerebral ischemia-induced neuroinflammation: Involvement of microglial M2 polarization via AMPK activation. European journal of pharmacology 21 32926919
2006 A minimum CR2 binding domain of C3d enhances immunity following vaccination. Advances in experimental medicine and biology 21 16893077
1996 Regulation of B cell growth and differentiation via CD21 and CD40. European journal of immunology 21 8814268

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