Affinage

CR2

Complement receptor type 2 · UniProt P20023

Length
1033 aa
Mass
112.9 kDa
Annotated
2026-04-28
100 papers in source corpus 41 papers cited in narrative 41 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

CR2 (CD21) is a complement receptor on B lymphocytes and follicular dendritic cells that links innate complement opsonization to adaptive humoral immunity by lowering the threshold for B cell activation, enhancing antigen processing, and supporting germinal center survival. Its two N-terminal short consensus repeats (SCR1-2) constitute a positively charged ligand-binding surface that engages complement C3 fragments (iC3b, C3dg, C3d), EBV glycoprotein gp350/220, and CD23, with C3d and gp350 sharing overlapping contact residues including R13, R28, R36, K41, K57, K67, and R83 (PMID:15713467, PMID:17925391). On B cells, CR2 associates with CD19, CD81, and Lyn kinase to form a coreceptor complex that, upon co-ligation with the BCR by complement-opsonized antigen, prolongs BCR residency in CD81-dependent lipid rafts, activates PI3-kinase signaling, upregulates c-FLIP to protect against Fas-mediated apoptosis, enhances antigen delivery to MHC class II compartments, and regulates CD19 surface density and PD-1 expression to calibrate B cell responsiveness (PMID:11239449, PMID:14688345, PMID:16116172, PMID:10753842, PMID:19710450). CR2 also serves as the obligate receptor for Epstein-Barr virus entry into B cells and T cells, with soluble recombinant SCR1-2 sufficient to block EBV infection and EBV-driven lymphoproliferation (PMID:1645784, PMID:32238579).

Mechanistic history

Synthesis pass · year-by-year structured walk · 14 steps
  1. 1984 High

    Establishing that a single surface glycoprotein mediates both complement C3d fragment binding and EBV attachment on B lymphocytes unified two previously separate receptor activities into one molecule, CR2/CD21.

    Evidence Transfer of CR2 from B cells to S. aureus particles conferred both C3d and EBV binding; anti-CR2 mAbs blocked both interactions

    PMID:6087328 PMID:6230668

    Open questions at the time
    • Ligand-binding domain within CR2 not yet localized
    • No structural information on the receptor
  2. 1985 High

    Mapping the CR2-binding site on C3 to residues 1199-1274 (critical region 1227-1232) and demonstrating CR2 expression on follicular dendritic cells established the molecular and cellular basis for complement-mediated antigen retention in germinal centers.

    Evidence CNBr fragment binding and peptide competition for C3 mapping; immunohistochemistry and immunoelectron microscopy for FDC localization

    PMID:2408276 PMID:2411809

    Open questions at the time
    • Functional significance of FDC-expressed CR2 for antibody responses not yet tested
    • Whether CR2 binding to C3 is sufficient for B cell activation unknown
  3. 1988 High

    Demonstrating that CR2 ligands enhance G1-to-S transition in PMA-activated B cells and that CR2 supports covalent C3 deposition and alternative pathway activation established CR2 as both a signaling receptor and a complement amplification platform.

    Evidence Thymidine incorporation with purified B cells and various CR2 ligands; immunoprecipitation showing ester-linked C3 on CR2, alternative pathway activation by purified CR2

    PMID:2459218 PMID:2831273

    Open questions at the time
    • Signaling intermediates downstream of CR2 not identified
    • Physiological relevance of CR2-mediated complement activation unclear
  4. 1989 High

    Identifying the EBV gp350 N-terminal peptide (EDPGFFNVE) as the CR2-binding epitope and measuring gp350-CR2 affinity (Kd ~3.2 nM, ~10,000-fold stronger than monomeric C3dg) revealed the molecular basis for EBV exploitation of CR2 and suggested multivalent C3d display is needed for physiological signaling.

    Evidence Synthetic peptide binding to purified CR2, competition inhibition of EBV infection; quantitative ligand binding by gel permeation chromatography and ultracentrifugation

    PMID:2464439 PMID:2555366

    Open questions at the time
    • Which SCR domains mediate ligand binding not yet resolved
    • How weak monomeric C3dg binding translates to B cell activation in vivo
  5. 1991 High

    Localizing all primary ligand-binding activity to SCR1-2 — sufficient to block both C3dg binding and EBV infection in vitro and lymphoproliferative disease in SCID mice — defined the minimal functional unit of CR2.

    Evidence Recombinant SCR1-2 expression in E. coli and insect cells; ELISA binding, proliferation inhibition, SCID mouse EBV lymphoma model

    PMID:1645784

    Open questions at the time
    • Atomic-resolution contacts between SCR1-2 and ligands unknown
    • Role of remaining SCRs in vivo not addressed
  6. 1992 High

    Identifying CD23 as a third CR2 ligand that drives IgE production upon CR2 engagement expanded CR2's role beyond complement to IgE class-switch regulation.

    Evidence CD23-bearing fluorescent liposomes bound CD21-transfected BHK cells; anti-CD21/soluble CD23 enhanced IL-4-induced IgE production

    PMID:1386409

    Open questions at the time
    • CD23-binding site on CR2 only partially mapped
    • Relative contribution of CD23-CR2 vs. CD23-IgE axis to IgE regulation in vivo unknown
  7. 1993 High

    Dissecting the CD19/CR2/TAPA-1 complex architecture and identifying Lyn kinase association established the coreceptor as a multi-subunit signaling module rather than a simple adhesion receptor.

    Evidence Domain-swap chimeras in Daudi B cells with Ca2+ and PI3-kinase readouts; co-immunoprecipitation showing Lyn in the CR2/CD19 complex

    PMID:7690241 PMID:7690834

    Open questions at the time
    • Stoichiometry and assembly order of the complex unknown
    • Direct contribution of CR2 cytoplasmic tail to signaling not defined
  8. 2001 High

    Three convergent 2001 studies established that complement-tagged antigen co-ligation prolongs BCR-CD19/CD21 residency in lipid rafts, enhances MHC class II antigen presentation via CR2 signaling, and that a lupus-associated Cr2 polymorphism introduces aberrant glycosylation disrupting C3d binding and receptor dimerization.

    Evidence Lipid raft fractionation and BCR internalization assays; B cell antigen processing with rHEL-C3d3; NZM2410 Cr2 sequencing, binding assays, and molecular modeling

    PMID:11239449 PMID:11418645 PMID:11728339

    Open questions at the time
    • Whether raft partitioning requires CD81 not yet tested
    • Structural basis for CR2 dimerization at atomic level unknown
    • Link between lupus Cr2 variant and disease causation not genetically proven
  9. 2004 High

    Demonstrating that CD81 is required for CD19/CD21 complex partitioning into lipid rafts resolved how the tetraspanin component enables enhanced BCR signaling upon complement coreceptor engagement.

    Evidence Lipid raft fractionation in CD81-knockout B cells and chimeric CD19 with weak CD81 association

    PMID:14688345

    Open questions at the time
    • Molecular mechanism by which CD81 drives raft association unknown
    • Whether CD81 affects CR2-independent signaling not addressed
  10. 2005 High

    Systematic mutagenesis of CR2 SCR1-2 and NMR structural analysis of the CD23 lectin domain resolved the charged interaction surfaces for C3d, gp350, and CD23 binding, showing that C3d and gp350 share overlapping positively charged contact residues while CD23 recognizes both SCR1-2 and SCR5-8 through distinct, calcium-independent sites.

    Evidence Site-directed mutagenesis with flow cytometry binding on K562 cells; NMR chemical shift perturbation mapping of CD23; epitope mapping with anti-CD21 mAbs

    PMID:15713467 PMID:16172256 PMID:7542093

    Open questions at the time
    • Full co-crystal structure of CR2 with any ligand not available at this point
    • Whether overlapping binding sites create ligand competition in vivo unknown
  11. 2005 High

    Showing that CR2/CD19 signaling upregulates c-FLIP to protect activated B cells from Fas-mediated death, with genetic rescue by lpr mutation, established CR2 as a survival signal in the germinal center reaction.

    Evidence Adoptive transfer of Cr2−/− B cells, c-FLIP quantitation, Cr2−/−lpr double mutant rescue

    PMID:16116172

    Open questions at the time
    • Signaling intermediates between CR2/CD19 and c-FLIP transcription not identified
    • Whether this anti-apoptotic function operates in human GC B cells unknown
  12. 2007 High

    Reciprocal bone marrow transfers attributing prion splenic retention to stromal (FDC) CD21/35 and mutagenesis confirming gp350-CR2 contact residues extended the functional importance of CR2 beyond classical immunity to infectious disease pathogenesis.

    Evidence Reciprocal BM transfers between CR2/35 WT and KO mice for prion; site-directed mutagenesis of CR2 for gp350 binding

    PMID:17925391 PMID:17947689

    Open questions at the time
    • Mechanism by which FDC-CR2 retains prions not elucidated
    • Whether CR2-prion interaction is direct or complement-mediated not resolved
  13. 2009 High

    Precision knockin mice and multi-KO epistasis experiments separated CR2's complement-dependent coreceptor signaling from a complement-independent role in regulating CD19 surface density and PD-1 expression, revealing dual mechanisms by which CR2 tunes B cell activation thresholds.

    Evidence Cr2ΔΔgfp knockin allowing C3 binding without CD19 signaling; comparison of CD21/35 KO, C3 KO, and C4 KO mice with PD-1 blockade rescue

    PMID:19706534 PMID:19710450

    Open questions at the time
    • How CR2 regulates CD19 surface density mechanistically unknown
    • Relative contribution of each pathway during natural infection not quantified
  14. 2020 High

    CRISPR knockout of CD21 in Jurkat T cells established CR2 as the obligate EBV entry receptor on mature T cells, extending CR2's viral receptor function beyond B lymphocytes.

    Evidence CRISPR-Cas9 CD21 KO in Jurkat cells abolished EBV-2 entry; anti-gp350 neutralization confirmed ligand dependence

    PMID:32238579

    Open questions at the time
    • How CR2 expression is regulated on T cells unknown
    • Post-entry viral lifecycle in T cells not characterized via CR2 engagement

Open questions

Synthesis pass · forward-looking unresolved questions
  • A high-resolution co-crystal structure of CR2 SCR1-2 simultaneously bound to C3d and gp350 is still needed to resolve whether the overlapping binding surfaces create true competition or allosteric modulation, and the signaling cascade linking CR2/CD19 co-engagement to c-FLIP upregulation and CD19 surface regulation remains molecularly undefined.
  • No ternary complex structure of CR2-C3d-gp350
  • Signaling intermediates between CR2/CD19 raft entry and c-FLIP induction uncharacterized
  • Mechanism of complement-independent CD19 regulation by CR2 unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0001618 virus receptor activity 4 GO:0060089 molecular transducer activity 4 GO:0098772 molecular function regulator activity 2
Localization
GO:0005886 plasma membrane 4
Pathway
R-HSA-168256 Immune System 8 R-HSA-162582 Signal Transduction 5 R-HSA-1643685 Disease 4 GO:0005886 plasma membrane 1
Partners
C3CD19CD23CD81CR1EBV GP350/220LYN
Complex memberships
CD19/CD21/CD81 (TAPA-1) B cell coreceptor complex

Evidence

Reading pass · 41 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1984 CR2 (CD21) was identified as the C3d receptor of human B lymphocytes (Mr 145,000 membrane protein) that binds complement fragments iC3b, C3d,g, and C3d; transfer of CR2 from B cells to protein A-bearing S. aureus particles conferred C3d/iC3b binding activity on those particles. Monoclonal antibody blocking (HB-5), rosette inhibition assay, immunoadsorption transfer experiment Proceedings of the National Academy of Sciences of the United States of America High 6087328 6230668
1984 CR2 (CD21) is the Epstein-Barr virus receptor of human B lymphocytes; monoclonal antibodies to CR2 block EBV binding, and transfer of CR2 to S. aureus particles confers EBV-binding capacity. Flow cytometry with anti-CR2 mAbs, EBV binding blockade, immunoadsorption transfer experiment Proceedings of the National Academy of Sciences of the United States of America High 6087328
1985 The CR2-binding site on C3 was mapped to an 8.6 kDa CNBr fragment corresponding to residues 1199-1274 of C3, with the CR2-binding site localized to residues 1227-1232. CNBr cleavage of C3d, peptide binding studies, amino-terminal sequence analysis Proceedings of the National Academy of Sciences of the United States of America High 2408276
1985 Follicular dendritic cells (FDC) express CR2 (as well as CR1 and CR3) on their entire plasma membrane and cytoplasmic extensions in germinal centers, providing a structural basis for FDC to capture complement-opsonized immune complexes. Immunohistochemistry (immunoperoxidase) and immunoelectron microscopy with anti-CR2 monoclonal antibodies on frozen lymph node sections Journal of immunology Medium 2411809
1986 CR2 undergoes phosphorylation in B lymphocytes upon PMA stimulation (via protein kinase C activation), in contrast to CR1 which is only phosphorylated in phagocytic cells, suggesting CR2 (not CR1) mediates PMA-induced regulation of B lymphocyte function. 32PO4 metabolic labeling, SDS-PAGE, autoradiography after PMA stimulation of multiple cell types The Journal of experimental medicine Medium 3484510
1987 Purified CR2 acts as a cofactor for factor I-mediated cleavage of membrane-bound iC3b (releasing C3c), demonstrating CR2 has regulatory activity in the complement cascade similar to CR1. In vitro enzyme assay with purified CR2 and factor I, inhibition with anti-CR2 mAb OKB7 The Journal of experimental medicine Medium 2437238
1987 A spontaneously shed 72-kDa proteolytic fragment of CR2 (gp72) retains the C3d-binding site and the OKB7 epitope, indicating the C3d-binding domain resides in the N-terminal portion of the receptor. Immunoprecipitation, affinity chromatography, flow cytometry, and radioimmune assay comparing intact CR2 and shed gp72 Complement Medium 3497773
1988 CR2 is a complement activator that serves as a major covalent (ester bond) and non-covalent binding site for C3 deposition on Raji cells during alternative pathway activation; purified CR2 alone can activate the alternative complement pathway. Immunoprecipitation with anti-CR2 and anti-C3 antibodies, hydroxylamine treatment to demonstrate ester linkage, in vitro alternative pathway activation assay with purified CR2 Journal of immunology High 2831273
1988 CR2 ligands (aggregated/latex-bound C3dg, anti-CR2 mAb OKB7) enhance the transition of PMA-activated B cells from G1 to S phase, whereas monomeric C3dg is inhibitory; the effect is T cell- and monocyte-independent. Thymidine incorporation assay with purified resting tonsil B cells, various CR2 ligands, and PMA activation Journal of immunology Medium 2459218
1989 The N-terminal region (EDPGFFNVE) of EBV gp350/220 contains the CR2-binding epitope; this peptide binds purified CR2 and CR2-positive cells, blocks EBV binding to CR2, and inhibits EBV-induced B cell proliferation and transformation. Synthetic peptide binding to purified CR2, competition binding assays, EBV-induced proliferation inhibition assay Cell High 2464439
1989 Soluble recombinant CR2 (rCR2) is a highly extended, flexible molecule composed of ring-like short consensus repeat domains (~24 Å each); gp350/220 binds rCR2 with Kd ~3.2 nM (saturable, univalent), whereas monomeric C3dg binds ~10,000-fold more weakly under physiological conditions. Gel permeation chromatography, density gradient ultracentrifugation, circular dichroism, high-resolution electron microscopy, quantitative ligand binding studies The Journal of biological chemistry High 2555366
1989 Cross-linking of CR2 by mIgM ligation leads to heterologous desensitization of CD21 such that subsequent CR2 ligation fails to mobilize Ca2+; this desensitization reflects uncoupling from G proteins rather than receptor downregulation. Ca2+ mobilization assay in EBV-transformed B cell lines and peripheral blood B cells, AIF4- control to confirm G protein coupling Proceedings of the National Academy of Sciences of the United States of America Medium 1701054
1990 Soluble recombinant CR2 substantially inhibits EBV infection of B cells in vitro, demonstrating that CR2 binding is required to initiate (not merely attach) EBV infection. In vitro EBV infection inhibition assay with soluble recombinant CR2 Journal of virology Medium 2154612
1991 Recombinant CR2 containing only SCR1-2 retains full ligand-binding activity for both C3dg and EBV gp350/220 and blocks EBV-induced B cell proliferation in vitro and EBV lymphoproliferative disease in SCID mice, localizing the primary ligand-binding domain to the two N-terminal SCRs. Recombinant protein expression (E. coli and insect cells), ELISA binding assay, in vitro proliferation inhibition, SCID mouse model Journal of virology High 1645784
1991 Multiple distinct sites in C3 (in C3c and C3d portions as well as the N-terminus of the alpha chain, residues 741-757) interact with CR2, explaining how multivalent C3-opsonized particles support B cell activation through CR2. Competitive binding assays with synthetic C3 peptides, microsphere-based CR2 binding, monoclonal antibody blocking European journal of immunology Medium 1834472
1992 CD21 (CR2) on B cells is a direct ligand for CD23 (FcεRII); CD23-bearing fluorescent liposomes bind specifically to CD21-expressing cells and CD21-transfected BHK-21 cells, and CD21 triggering by anti-CD21 antibody or soluble CD23 enhances IL-4-induced IgE production. Fluorescent CD23-liposome binding assay, CD21-cDNA transfection, Western blot, IgE production assay from blood mononuclear cells Nature High 1386409
1993 CR2 (CD21) and CD19 interact through their extracellular and transmembrane domains; CD19 and TAPA-1 interact through extracellular domains; CR2 and CR1/CD35 interact through extracellular domains. Chimeric CD19 lacking the CD21/TAPA-1 interaction retains synergistic Ca2+ signaling and PI3-kinase association with mIgM but loses homotypic aggregation (a TAPA-1 function). Domain-swap chimeric molecule expression in Daudi B cells, intracellular Ca2+ measurement, PI3-kinase association assay, homotypic aggregation assay The Journal of experimental medicine High 7690834
1993 The CD19/CR2 complex on human B cells contains the src-family kinase Lyn; CD19 is tightly linked to Lyn and CD19 itself serves as a substrate for a serine/threonine kinase present within the complex. Co-immunoprecipitation of the CR2/CD19 complex followed by kinase assay International immunology Medium 7690241
1993 CD21 expressed on basophilic cells mediates CD23 binding and triggers histamine release upon CD23 or anti-CD21 mAb stimulation, demonstrating a functional CD23-CD21 interaction on non-B cells. CD23-liposome binding assay on KU 812 basophilic cell line, anti-CD21 blocking, mRNA detection, histamine release assay with normal blood basophils European journal of immunology Medium 7691616
1995 CD23 recognizes two main epitope regions on CD21: SCR1-2 and SCR5-8; Asn370 and Asn295 within SCR5-8 are critical for CD23-CD21 interaction, and CD23-CD21 engagement preferentially drives IgE production. Epitope mapping with anti-CD21 antibodies to distinct SCR regions, IgE production assay International archives of allergy and immunology Medium 7542093
1995 A C3d-binding site on CR2 was characterized by human-mouse CR2 chimeras; an important region in SCR1 (same sequence involved in OKB7 and EBV binding) and a new region in SCR2 both contribute to iC3b binding. Human-mouse CR2 chimeras, blocking mAb 4E3, human CR2-derived peptides, complement binding assays Journal of immunology Medium 7730644
1996 Cross-linking of CR2 (CD21) by EBV gp350/220 induces IL-6 mRNA and protein in B cells via PKC- and protein tyrosine kinase-dependent pathways, blocked by anti-gp350/220 and anti-CD21 mAbs. EBV and recombinant gp350/220 stimulation of B cells, cytokine ELISA/mRNA detection, kinase inhibitor studies, anti-CD21 blocking Journal of virology Medium 8523572
1998 FDC-expressed CR2/CD21 bearing complement C3 fragments as ligand provides a critical co-stimulatory signal for B cell IgG responses; soluble CR2 or CR2 knockout B cells reduce antibody responses 10-1000-fold, and FDC from C3-knockout mice lack co-stimulatory activity. In vitro antibody response assay with FDC, soluble CR2 blocking, CR2 knockout mouse B cells, C3 knockout mouse FDC Journal of immunology High 9794381
2000 C3dg-conjugated antigen is internalized by CR2 on B cells via coated pits at the bases of microvilli and delivered to multivesicular/multilaminar endocytic compartments containing MHC class II molecules, directly linking CR2 to antigen processing/presentation. Electron microscopy with C3dg-colloidal gold conjugates, CR2 blocking antibody, immunolabeling for MHC class II Blood High 10753842
2001 Binding of complement-tagged antigens co-ligates BCR and CD19/CD21 complex into plasma membrane lipid rafts, prolonging BCR residency and signaling in rafts and retarding BCR internalization and degradation. Lipid raft fractionation, BCR internalization assay, signaling assays in B cells with complement-tagged antigens Immunity High 11239449
2001 CD21/CR2 co-engagement with BCR enhances antigen processing efficiency, producing more rapid and efficient antigenic peptide/MHC class II complexes; this effect operates through CR2's signaling function rather than by direct targeting of antigen for processing. B cell antigen processing assay with rHEL-C3d3 recombinant protein, peptide/MHC class II complex detection Journal of immunology Medium 11418645
2001 The NZM2410 Cr2 allele contains a single nucleotide polymorphism introducing a novel glycosylation site in the C3d binding domain, resulting in higher molecular weight CR2 proteins with reduced C3d ligand binding and receptor-mediated signaling; molecular modeling shows this glycosylation disrupts receptor dimerization. Sequencing, functional C3d binding assays, cell signaling assays, molecular modeling based on CR2-C3d crystal structure Immunity High 11728339
2001 CR2/CD21 is required for EBV entry into epithelial cells (293 cell line); low-level CD21 surface expression supports EBV infection that is blocked by anti-CD21 antibody, even in the absence of CD19 or CD35. EBV infection of CD21-expressing 293 cells, anti-CD21 antibody blocking, flow cytometry, EBV gene expression analysis Journal of virology Medium 9971794
2001 EBV gp350/220 binding to CR2 activates NF-κB and induces IL-6 gene expression in B cells via PKC pathway (for gp350 alone) or multiple signaling pathways (for whole EBV), with EBV inducing longer-lived IL-6 mRNA than gp350 alone. IL-6 mRNA and protein quantitation, NF-κB band-shift assay, CAT reporter assay, PKC inhibitor, kinase inhibitor studies Journal of molecular biology Medium 11327783
2004 CD81 (tetraspanin) is required for the CD19/CD21 complex to partition into signaling-active lipid rafts upon BCR co-ligation; in CD81-deficient B cells or cells expressing chimeric CD19 with weak CD81 association, coligated BCR and CD19/CD21 fail to enter lipid rafts and enhanced signaling is lost. Lipid raft fractionation in CD81 knockout B cells, chimeric CD19 expression, signaling assays Journal of immunology High 14688345
2005 Mutational analysis of CR2 SCR1-2 identified that mutations at the SCR2-C3d interface (R83A, R83E, G84Y) strongly disrupt C3dg binding, and positively charged residues on SCR1 (R13, R28, R36, K41, K50, K57, K67) also contribute to a direct SCR1-C3d binding site. Site-directed mutagenesis, K562 cell surface expression of wild-type and mutant CR2, C3dg-biotin tetramer flow cytometry binding assay Journal of molecular biology High 15713467
2005 The three-dimensional NMR structure of the CD23 C-type lectin domain was determined; distinct binding sites for IgE and CD21 were identified on CD23, CD23 can bind both ligands simultaneously, and CD23-IgE interaction can form high-molecular-mass multimeric complexes; none of these interactions require calcium despite the C-type lectin structure. NMR spectroscopy, chemical shift perturbation mapping for IgE and CD21 binding sites, gel filtration for complex analysis The Journal of experimental medicine High 16172256
2005 CD21/CD19 co-receptor signaling protects activated B cells from CD95 (Fas)-mediated apoptosis by upregulating c-FLIP; Cr2-deficient B cells have reduced c-FLIP levels and are eliminated via CD95 pathway, rescued by Cr2-/- lpr mutation. Adoptive transfer model, flow cytometric survival analysis, c-FLIP Western blot and mRNA quantitation, in vitro culture with rHEL-C3d3 Journal of immunology High 16116172
2005 Conjugation of C3d to antigen is sufficient to cause collagen-induced arthritis in the absence of CFA; CD19- and CD21-deficient mice are not susceptible to CIA; adoptive transfer showed CR2 on either B cells or FDCs is sufficient for disease susceptibility. DBA/1 collagen-induced arthritis model with C3d-conjugated antigen, CD19 and CD21 knockout mice, adoptive transfer experiments Journal of immunology High 16210644
2007 The gp350 binding site on CR2 maps to a large contiguous surface of SCR1-2 involving multiple positively charged residues (R13, R28, R36, K41, K57, K67, R83) that are complementary to the electronegative CR2-binding site on gp350; both SCR1 and SCR2 make contact with gp350. Site-directed mutagenesis of CR2 expressed on K562 cells, gp350 flow cytometry binding assay, anti-CR2 mAb epitope competition The Journal of biological chemistry High 17925391
2007 Stromal (follicular dendritic cell) CD21/35 expression, but not hematopoietic CD21/35, is responsible for splenic retention and prion replication; reciprocal bone marrow transfers showed protection arose from stromal CD21/35 ablation. Reciprocal bone marrow adoptive transfer between CR2/35 WT and KO mice, prion infectivity assay, double KO (PrPC−/−;CD21/35−/−) transfer experiments Journal of immunology High 17947689
2007 CD21 (CR2) expressed on myeloma cells mediates adhesion to bone marrow stromal cells via CD23 on stromal cells; anti-CD21 and anti-CD23 antibodies inhibit myeloma-stroma adhesion. Adhesion inhibition assay with myeloma cell lines and BM stromal cells, anti-CD21 and anti-CD23 monoclonal antibody blocking Blood Medium 7780154
2009 Uncoupling CR2 from CD19 (by knockin mutation allowing C3 ligand binding but abolishing CD19 signaling) significantly impairs germinal center B cell survival and secondary antibody titers but preserves some B cell memory, identifying a CD19-independent role for CR2 in B-cell memory. Knockin mouse (Cr2ΔΔgfp) generating CR2 that binds C3 but does not signal through CD19; GC B cell flow cytometry, antibody titer measurement Proceedings of the National Academy of Sciences of the United States of America High 19706534
2009 CD21/35 promotes protective humoral immunity to TI-2 antigens through a complement-independent mechanism by negatively regulating CD19 expression and PD-1 induction; reducing CD19 in CD21/35-deficient mice rescues BCR signaling and IgG3 responses. CD21/35 KO vs. C3 KO vs. C4 KO mice; flow cytometry for CD19, PD-1, and BCR-induced Ca2+ responses; PD-1 blockade experiment Journal of immunology High 19710450
2020 CD21 (CR2) is required for EBV entry into mature T cells; viral gp350 and CD21 are both necessary for EBV-2 infection of CD3+ T cells, and CRISPR-Cas9 knockout of CD21 in Jurkat cells abolishes EBV entry. Neutralizing antibody assay, CRISPR-Cas9 CD21 knockout in Jurkat cells, ex vivo infection model Journal of virology High 32238579
2001 The CR2/CD21 intronic silencer requires a CBF1 (RBP-J/Notch signaling component) binding site for lineage-specific transcriptional repression; a 2-bp mutation eliminating CBF1 binding abolishes silencer activity, demonstrating Notch pathway involvement in restricting CR2 expression to mature B cells. Stable transfection of mutant silencer constructs, transgenic mouse reporter assays, in vitro binding assays International immunology Medium 11312253

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 380 20231422
2000 Regulation of B lymphocyte responses to foreign and self-antigens by the CD19/CD21 complex. Annual review of immunology 374 10837064
1984 Identification of a 145,000 Mr membrane protein as the C3d receptor (CR2) of human B lymphocytes. Proceedings of the National Academy of Sciences of the United States of America 275 6230668
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 218 28783670
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 189 23279883
2002 Expansion of CD19(hi)CD21(lo/neg) B cells in common variable immunodeficiency (CVID) patients with autoimmune cytopenia. Immunobiology 177 12607725
2001 The CD19/CD21 complex functions to prolong B cell antigen receptor signaling from lipid rafts. Immunity 164 11239449
1989 Identification of an epitope in the major envelope protein of Epstein-Barr virus that mediates viral binding to the B lymphocyte EBV receptor (CR2). Cell 164 2464439
2007 Complement receptors CD21 and CD35 in humoral immunity. Immunological reviews 141 17850488
2001 Cr2, a candidate gene in the murine Sle1c lupus susceptibility locus, encodes a dysfunctional protein. Immunity 135 11728339
2001 The role of the CD19/CD21 complex in B cell processing and presentation of complement-tagged antigens. Journal of immunology (Baltimore, Md. : 1950) 129 11418645
1986 Tissue-specific phosphorylation of complement receptors CR1 and CR2. The Journal of experimental medicine 125 3484510
2021 The expansion of human T-bethighCD21low B cells is T cell dependent. Science immunology 120 34623902
2005 The structure of human CD23 and its interactions with IgE and CD21. The Journal of experimental medicine 112 16172256
2004 The tetraspanin CD81 is necessary for partitioning of coligated CD19/CD21-B cell antigen receptor complexes into signaling-active lipid rafts. Journal of immunology (Baltimore, Md. : 1950) 111 14688345
2009 Differential expression of CD21 identifies developmentally and functionally distinct subsets of human transitional B cells. Blood 109 19965666
2002 Complement receptors CD21/35 link innate and protective immunity during Streptococcus pneumoniae infection by regulating IgG3 antibody responses. Immunity 101 12479818
1988 CR2 ligands modulate human B cell activation. Journal of immunology (Baltimore, Md. : 1950) 101 2459218
1985 Mapping of the C3d receptor (CR2)-binding site and a neoantigenic site in the C3d domain of the third component of complement. Proceedings of the National Academy of Sciences of the United States of America 94 2408276
1998 Evidence for an important interaction between a complement-derived CD21 ligand on follicular dendritic cells and CD21 on B cells in the initiation of IgG responses. Journal of immunology (Baltimore, Md. : 1950) 88 9794381
1989 Hydrodynamic, electron microscopic, and ligand-binding analysis of the Epstein-Barr virus/C3dg receptor (CR2). The Journal of biological chemistry 82 2555366
2004 CR1/CR2 interactions modulate the functions of the cell surface epidermal growth factor receptor. The Journal of biological chemistry 78 15016810
1993 The CR2/CD19 complex on human B cells contains the src-family kinase Lyn. International immunology 76 7690241
1993 The CD19-CR2-TAPA-1 complex, CD45 and signaling by the antigen receptor of B lymphocytes. Current opinion in immunology 75 7688513
2002 Functional activity of natural antibody is altered in Cr2-deficient mice. Journal of immunology (Baltimore, Md. : 1950) 70 12421918
2015 CD21 -/low B cells: A Snapshot of a Unique B Cell Subset in Health and Disease. Scandinavian journal of immunology 69 26119182
2008 Comparative functional evolution of human and mouse CR1 and CR2. Journal of immunology (Baltimore, Md. : 1950) 67 18713965
1999 CD21-Dependent infection of an epithelial cell line, 293, by Epstein-Barr virus. Journal of virology 66 9971794
2022 Human T-bet governs the generation of a distinct subset of CD11chighCD21low B cells. Science immunology 65 35867801
2001 CD19, CD21, and CD22: multifaceted response regulators of B lymphocyte signal transduction. International reviews of immunology 64 11913948
2000 A role for CD21/CD35 and CD19 in responses to acute septic peritonitis: a potential mechanism for mast cell activation. Journal of immunology (Baltimore, Md. : 1950) 62 11120817
2007 Stromal complement receptor CD21/35 facilitates lymphoid prion colonization and pathogenesis. Journal of immunology (Baltimore, Md. : 1950) 57 17947689
2007 High CD21 expression inhibits internalization of anti-CD19 antibodies and cytotoxicity of an anti-CD19-drug conjugate. British journal of haematology 57 17991300
2002 A role for the Cr2 gene in modifying autoantibody production in systemic lupus erythematosus. Journal of immunology (Baltimore, Md. : 1950) 56 12133988
1988 CR2 is a complement activator and the covalent binding site for C3 during alternative pathway activation by Raji cells. Journal of immunology (Baltimore, Md. : 1950) 56 2831273
2004 Cutting edge: C3d functions as a molecular adjuvant in the absence of CD21/35 expression. Journal of immunology (Baltimore, Md. : 1950) 53 15128761
2013 Peripheral CD27-CD21- B-cells represent an exhausted lymphocyte population in hepatitis C cirrhosis. Clinical immunology (Orlando, Fla.) 52 24434272
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 47 21884592
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
2020 CD21 (Complement Receptor 2) Is the Receptor for Epstein-Barr Virus Entry into T Cells. Journal of virology 46 32238579
1996 Induction of interleukin-6 after stimulation of human B-cell CD21 by Epstein-Barr virus glycoproteins gp350 and gp220. Journal of virology 46 8523572
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
1989 Proliferation of resting B cells is modulated by CR2 and CR1. Immunology letters 44 2527816
2005 A critical role for complement C3d and the B cell coreceptor (CD19/CD21) complex in the initiation of inflammatory arthritis. Journal of immunology (Baltimore, Md. : 1950) 43 16210644
2001 Epstein-Barr Virus and its glycoprotein-350 upregulate IL-6 in human B-lymphocytes via CD21, involving activation of NF-kappaB and different signaling pathways. Journal of molecular biology 43 11327783
2005 Mutational analysis of the complement receptor type 2 (CR2/CD21)-C3d interaction reveals a putative charged SCR1 binding site for C3d. Journal of molecular biology 42 15713467
2022 A close-up on the expanding landscape of CD21-/low B cells in humans. Clinical and experimental immunology 41 36380692
2000 Tracing uptake of C3dg-conjugated antigen into B cells via complement receptor type 2 (CR2, CD21). Blood 41 10753842
1995 Characterization of a complement receptor 2 (CR2, CD21) ligand binding site for C3. An initial model of ligand interaction with two linked short consensus repeat modules. Journal of immunology (Baltimore, Md. : 1950) 41 7730644
1991 Evidence for multiple sites of interaction in C3 for complement receptor type 2 (C3d/EBV receptor, CD21). European journal of immunology 41 1834472
1990 Ligation of membrane immunoglobulin leads to inactivation of the signal-transducing ability of membrane immunoglobulin, CD19, CD21, and B-cell gp95. Proceedings of the National Academy of Sciences of the United States of America 41 1701054
1987 Functional and antigenic properties of complement receptor type 2, CR2. The Journal of experimental medicine 41 2437238
2005 Complement component C3d-antigen complexes can either augment or inhibit B lymphocyte activation and humoral immunity in mice depending on the degree of CD21/CD19 complex engagement. Journal of immunology (Baltimore, Md. : 1950) 40 16339538
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
2021 New aspects in the regulation of human B cell functions by complement receptors CR1, CR2, CR3 and CR4. Immunology letters 38 34186155
2020 The Antigen Presenting Potential of CD21low B Cells. Frontiers in immunology 38 33193306
2005 CD21/CD19 coreceptor signaling promotes B cell survival during primary immune responses. Journal of immunology (Baltimore, Md. : 1950) 38 16116172
1989 Soluble forms of CD21 and CD23 antigens in the serum in B cell chronic lymphocytic leukaemia. Immunology letters 38 2523865
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
2002 Transmission of antibody-induced arthritis is independent of complement component 4 (C4) and the complement receptors 1 and 2 (CD21/35). European journal of immunology 37 11857338
1995 Expression of CD21 antigen on myeloma cells and its involvement in their adhesion to bone marrow stromal cells. Blood 37 7780154
1991 Inhibition of Epstein-Barr virus infection in vitro and in vivo by soluble CR2 (CD21) containing two short consensus repeats. Journal of virology 37 1645784
1993 Complement-mediated binding of naturally glycosylated and glycosylation-modified human immunodeficiency virus type 1 to human CR2 (CD21). Journal of virology 35 8474169
2017 High SYK Expression Drives Constitutive Activation of CD21low B Cells. Journal of immunology (Baltimore, Md. : 1950) 34 28468967
2011 Double-positive CD21+CD27+ B cells are highly proliferating memory cells and their distribution differs in mucosal and peripheral tissues. PloS one 33 21304587
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 31 14719373
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
2021 T-bet+CD27+CD21- B cells poised for plasma cell differentiation during antibody-mediated rejection of kidney transplants. JCI insight 30 34032636
1999 Hodgkin's disease expressing follicular dendritic cell marker CD21 without any other B-cell marker: a clinicopathologic study of nine cases. The American journal of surgical pathology 30 10199466
1987 Identification of a spontaneously shed fragment of B cell complement receptor type two (CR2) containing the C3d-binding site. Complement (Basel, Switzerland) 30 3497773
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
2018 Accumulation of Antigen-Driven Lymphoproliferations in Complement Receptor 2/CD21-/low B Cells From Patients With Sjögren's Syndrome. Arthritis & rheumatology (Hoboken, N.J.) 28 29073352
2016 The Structure-Function Relationships of Complement Receptor Type 2 (CR2; CD21). Current protein & peptide science 28 26916158
1999 Targeting of influenza epitopes to murine CR1/CR2 using single-chain antibodies. Immunopharmacology 28 10408376
1995 Role of Epstein-Barr virus and soluble CD21 in persistent polyclonal B-cell lymphocytosis. British journal of haematology 28 7646990
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 27 36931129
2007 Isolating the Epstein-Barr virus gp350/220 binding site on complement receptor type 2 (CR2/CD21). The Journal of biological chemistry 27 17925391
2021 CD27-CD38lowCD21low B-Cells Are Increased in Axial Spondyloarthritis. Frontiers in immunology 26 34168654
2012 Genetic depletion of complement receptors CD21/35 prevents terminal prion disease in a mouse model of chronic wasting disease. Journal of immunology (Baltimore, Md. : 1950) 26 23002439
2009 CD21/35 promotes protective immunity to Streptococcus pneumoniae through a complement-independent but CD19-dependent pathway that regulates PD-1 expression. Journal of immunology (Baltimore, Md. : 1950) 26 19710450
2004 CR1/CR2 deficiency alters IgG3 autoantibody production and IgA glomerular deposition in the MRL/lpr model of SLE. Autoimmunity 26 15293881
2003 Decreased levels of serum soluble complement receptor-II (CR2/CD21) in patients with rheumatoid arthritis. Rheumatology (Oxford, England) 26 12867574
2000 Quantitative expression of CD23 and its ligand CD21 in chronic lymphocytic leukemia. Haematologica 26 11064465
1986 Characterization of monoclonal antihuman-B-cell antibody BL13 as an anti-C3d-receptor (CR2) antibody. Scandinavian journal of immunology 26 2419969
2017 Reversion of anergy signatures in clonal CD21low B cells of mixed cryoglobulinemia after clearance of HCV viremia. Blood 25 28507081
2004 Reduction of soluble complement receptor 2/CD21 in systemic lupus erythomatosus and Sjogren's syndrome but not juvenile arthritis. Scandinavian journal of immunology 25 15584974
2003 Regulation of B-cell activation by complement receptors CD21 and CD35. Current pharmaceutical design 25 12871189
1993 CD21 expressed on basophilic cells is involved in histamine release triggered by CD23 and anti-CD21 antibodies. European journal of immunology 25 7691616
1990 Deficiencies of human C3 complement receptors type 1 (CR1, CD35) and type 2 (CR2, CD21). Immunodeficiency reviews 25 2164822
2019 TNF-Induced Interstitial Lung Disease in a Murine Arthritis Model: Accumulation of Activated Monocytes, Conventional Dendritic Cells, and CD21+/CD23- B Cell Follicles Is Prevented with Anti-TNF Therapy. Journal of immunology (Baltimore, Md. : 1950) 24 31659014