CD21 CR2 (complement receptor type 2), EBV-receptor(Epstein Barr virus receptor), C3δ-receptor, gp140
Molecule TypeAntigen ExpressionMolecular Weight
Min / Max
Non-lineage Restricted Molecule
Type 1 glycoprotein
B Cell
Dendritic Cell
Epithelial Cell
Thymocyte
Marginal zone cell
T Cell
130 / 130
145 / 145

Expression
CD21 is expressed on mature B cells with strong expression in marginal zone cells,  moderate expression by follicular mantle zone B cells and no expression by germinal centre B cells.  B cells are on the stage when surface Ig is first expressed but is lost upon activation.  CD21 is also expressed on follicular dendritic cells and a subset of immature thymocytes.  Low density expression is detected on pharyngeal and cervical epithelial cells, fetal astrocytes, subsets of immature and normal thymocytes, T cells and T-ALL.  Some anti-CD21 mAbs bind epithelial cells.


Structure
MOLECULAR FAMILY NAME:  Belongs to the regulators of complement activation gene family.

CD21 is a single-pass type-1 glycoprotein.  It contains an extracellular domain which contains 15-16 short consensus repeats (SCR), with 15 to 16 complement control protein (CCP) domains tightly-folded units of about 60 aa  which are organized in at least 5 groups, that forms a minimum of 6 different epitopes, a 28 aa transmembrane domain and 34 aa C-terminal cytoplasmic tail containing potential protein kinases C and tyrosine kinase sites.  The CD21 gene is a member of the regulation of complement activation (RCA) gene cluster that encodes a family of C3/C4 binding proteins (see CD35).  SCR 1 and 2 have binding sites for C3 fragments and EBV that although distinct probably overlap.  SCR 3 and 4 bind soluble cross-linked C3δγ with high affinity.  CSR 5-8 have two distinct epitopes recognized by different mAbs.

MOLECULAR MASS
Cell Type Unreduced Reduced
B cells 145 kDa 110 kDa after endoglycosidase F treatement
Soluble 130 kDa

POST-TRANSCRIPTIONAL MODIFICATION

Alternative splicing yields 4 different isoforms.  SCR1 and 2 have binding sites for C3 fragments and EBV that probably overlap.  SCR3 and 4 bind soluble cross-linked C3δγ with high affinity.  SCR 5-8 have two distinct epitopes recognized by different mAbs.  The extra CCP at position 11 is supposed to be the product of alternative splicing.

POST-TRANSLATIONAL MODIFICATION

SCR 5-8 is suggested to be glycosylated, a N-linked oligosaccharide.

Ligands
CD21 is a receptor for the C3 activation fragments iC3b and C3δ.  It is also the receptor used by the Epstein-Barr virus (EBV) to infect B lymphocytes.  CD21 has been shown to bind CD23 and IFNa.   CD21 is also associated with CD35 on B cells.

LIGANDS AND MOLECULES ASSOCIATED WITH CD21
Molecule Comment
C3δ Ligand whose binding site located at SCR 1-2 (epitope different from Epstein Barr Virus [EBV])
Soluble crosslinked C3dg SCR 3-4 necessary for high affinity binding of C3dg
CD23 Ligand whose binding site located at SCR 5-8
CD19 CD19, CD21, CD81 and Leu13 form a signaling complex; ligands to CD21 can strongly enhance activation by this complex.

CD81 CD19, CD21, CD81 and Leu13 form a signaling complex; ligands to CD21 can strongly enhance activation by this complex.

Leu13 CD19, CD21, CD81 and Leu13 form a signaling complex; ligands to CD21 can strongly enhance activation by this complex.

Molecule on EBV Ligand whose binding site is located at SCR 1-2



Function
CD21 is a complement receptor 2 for Epstein Barr virus receptor (EBV), for C3δ, C3δγ, iC3b and binds to the breakdown products of the C3 complement component and may activate B cells through CD21.  CD21 is part of a large signal-transduction complex that also involves CD19, CD81, and Leu 13. IgM acts with CD21 in B cell activation.  High density expression on marginal B cells enables a rapid primary immune response in particular to T-cell independent antigens.  Co-valent antigen-complement complexes bind to the B cell antigen receptor, the BCR surface Ig, the simultaneous interaction of CD21 with the complement component C3δ enhances signaling through the BCR.  The CD21 signal, which is transduced through the associated molecules CD19 and CD81, very effectively lowers the activation threshold of the BCR.  Thus C3δ may be considered as a molecular adjuvant that directs the acquired immune response toward antigens recognized by the innate immune response.  Mice made defective in CD21 have an impaired immune response to T-dependent antigens.  The CD21/CD23 interaction may have a regulatory role in IgE production.  The murine knockouts show an important function of CD21 on B cells in both T cell-dependent and type 2 T-cell independent responses.

BIOCHEMICAL ACTIVITY: No information.

DISEASE RELEVANCE AND FUNCTION OF CD21 IN INTACT ANIMAL

CD21 is a surface marker useful in phenotypying malignant B-cell lymphomas and for immunohistologic study of follicular dendtritic cell patterns.  The combined demonstration of EBV and CD21 is used in the diagnosis of post-transplant lymphoproliferative disease.  The inability of infants below the age of two to make adequate antibody responses to polysaccharides is associated with the lack of CD21+ marginal zone B cells.


Comments
MOLECULAR INTERACTIONS -
PROTEINS AND DNA ELEMENTS WHICH REGULATE TRANSCRIPTION OF CD21: No information.

SUBSTRATES: No information.

ENZYMES WHICH MODIFY CD21: No information.

ADDITIONAL INSIGHTS

The high density of CD21 on splenic marginal zone B-cells suggests the possibility for rapid and easy activation in a primary immune response.  CD21 appears crucial in TI-1 response as for pneumococcal polysaccharides.

Database accession numbers
AnimalPIRSWISSPROTEMGBL/GENBANK
 
HumanEntrezgene 1380P20023
MouseA43526P19070M35684
Antibodies
B-Ly4   View Reactivity
BAQ15A   View Reactivity
BB6-11C9   View Reactivity
BL13   View Reactivity
CC21   View Reactivity
F46A   View Reactivity
GB25A   View Reactivity
LB21   View Reactivity
LCT21A   View Reactivity
LCT28A   View Reactivity

Revised June 25, 2008


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