CD305 LAIR-1 (leukocyte associated immunoglobulin-like receptor 1)
Molecule TypeAntigen ExpressionMolecular Weight
Min / Max
Non-lineage Restricted Molecule
Type 1 glycoprotein
Leukocyte
T Cell
B Cell
Monocyte
NK Cell
Dendritic Cell
Peripheral blood
Lymphocyte
31 / 31

Expression
CD305 is widely expressed in the human immune system.  It is expressed on the majority on the surface of  human peripheral blood mononuclear leukocytes, lymphocytes, NK cells, monocytes, dendritic cells including T and B cells.  Expression on B cells is related to the maturation stage of the B cells.  All naive B cells and about one half of memory B cells express CD305.  Germinal center B cells and plasma cells do not express the molecule.  NK cells and monocytes freshly isolated from peripheral blood are low or negative.  It is not expressed on monocyte derived dendritic cells cultured with GM-CSF plus IL-4 and or TNFa.   CD305 is not detected on platelets, erythrocytes or non-hematopoietic cells.  It is expressed on thymocytes, thymic precursors CD34+CD2-CD7+.  CD305 is located on the cell surface in contrast to CD306 (LAIR-2) which is a putative secreted protein.  Expression is abnormally low in naive B cells from HIV-1 infected patients and very low in NK cells from a patient with chronic active Epstein Barr virus infection.  There is a complete loss of expression when naive B cells proliferates and differentiates into Ig-producing plasma cells under in vitro stimulation.

Structure
MOLECULAR FAMILY NAME: Belongs to the immunoglobulin gene family.

CD305 is a single-pass type-1 287 aa transmembrane glycoprotein.  It contains a signal sequence, an 142 aa extracellular domain which contains a pair of cysteines that generate an Ig-like C2-type domain and a potential N-glycosylation site, a transmembrane domain and a 101 aa cytoplasmic domain that contains 2 immunoreceptor tyrosine based inhibitory motifs (ITIMs).  When phosphorylatyed, ITIM motif can bind the SH2 domain of several SH2-containing phostatases, leading to down-regulation of call activation.  There is a 2nd gene, CD306 (LAIR-2) which is closely related to CD305 (LAIR-1), having an 84% homology in the Ig-like domain but unlike CD305, CD306 lacks a transmembrane region and is predicted to be a secreted protein.
 
MOLECULAR MASS
Cell Type Unreduced Reduced Comment
PBMC 40 kDa or 32 kDa 40 kDa or 32 kDa Isoforms of LAIR-1 appear as 40 kDa or 32 kDa in molecular weight on reducing and non-reducing SDS-PAGE.  NK cells express both forms, while T cells seem to preferably express the smaller form of LAIR-1
NK cell clones 40 kDa or 32 kDa 40 kDa or 32 kDa Isoforms of LAIR-1 appear as 40 kDa or 32 kDa in molecular weight on reducing and non-reducing SDS-PAGE.  NK cells express both forms, while T cells seem to preferably express the smaller form of LAIR-1
Jurkat T cells 32 kDa 32 kDa Isoforms of LAIR-1 appear as 40 kDa or 32 kDa in molecular weight on reducing and non-reducing SDS-PAGE.  NK cells express both forms, while T cells seem to preferably express the smaller form of LAIR-1

POST-TRANSCRIPTIONAL MODIFICATION

Alternative splicing yield 4 different isoforms.  Isoform 2 contains 270aa, isoform 3 contains 269 aa as well as ITIMS.  The 209 aa isoform 4 lacks most of the intracellular cytoplasmic domain as well as the ITIMs and therefore canot bind SHP1.  Immunoprecipitation and immunoblot analyses determinted that the association of SHP1 and CD305 is a constitutive interaction.

POST-TRANSLATIONAL MODIFICATION

CD305 contains a potential site for N-linked glycosylation and the protein is modified by O-linked sugars.  It has been demonstrated that SHP1 is associated through its SH2 domain when CD305 is tyrosine-phosphorylated.

Ligands
CD305 is associated with Ep-CAM.

LIGANDS AND MOLECULES ASSOCIATED WITH CD305
Molecule Comment
SHP-1 tyrosine phosphatase Association occurs after tyrosine phosphorylation of the ITIM of LAIR-1
SHP-2 tyrosine phosphatase Association occurs after tyrosine phosphorylation of the ITIM of LAIR-1



Function
Upon cross-linking with antibodies, CD305 functions as an inhibitor of cell function and has been demonstrated in vitro with cross-linking by CD305 antibody inhibiting cytotoxicity by NK cells and activated T and B cells and these inhibitor receptors regulate the immune response to prevent lysis of cells recognized as self.  The ligand for CD305 has not been found so the physiological relevance of this inhibitory function is not known.  The cross-linking results in phosphorylation of the ITIM motifs, leading to inhibition of cellular activation.  There is a reduction in the increase of intracellular calcium evoked by the B cell receptor ligation and plays a role in its inhibitory role independently of SH2-containing phosphatases.  Cross-linking results in a decrease in cytotoxic activity in vitro by human NK cell clones, cytotoxic T lymphocytes and freshly isolated NK cells even in the presence of strongly activating signals.  After treatment of NK cells, tyrosine phosphorylated LAIR-1 recruits the SHP-1 and SHP-2 phosphatases.  Co-ligation of CD305 and surface Ig prevents B cell receptor-induced Ca++ mobilization by naive B cells.  CD305 cross-linking with antibodies results in decreased GM-CSF induced- differentiation of peripheral blood precursors into dendritic cells. The engagement inhibits T lymphocyte proliferation induced by anti-TCR specific antibodies and NK proliferation to IL-2 and inhibits spontaneous proliferation of myelomonocytic cell lines by blocking nuclear translocation of NF-kB.  Cytokine production is modulated in CD4+ T cells, down regulating IL-2 and IFN-γ production while inducing secretion of transforming growth factor beta.  There is down regulation of IgG and IgE production in B cells as well as IL-8, IL-10 and TNF secretion.  CD305 inhibits cellular activation and inflammation.  CD305 is structurally related to human killer cell inhibitory receptors, but does not appear to recognize HLA class I molecules and thus represents a novel HLA class I-independent mechanism of NK regulation.

BIOCHEMICAL ACTIVITY: No information.

DISEASE RELEVANCE AND FUNCTION OF CD305 IN INTACT ANIMAL

CD305 inhibits proliferation and induces apoptosis in myeloid leukemia cell lines. 


Comments
MOLECULAR INTERACTIONS -
PROTEINS AND DNA ELEMENTS WHICH REGULATE TRANSCRIPTION OF CD305: No information.

SUBSTRATES: No information.

ENZYMES WHICH MODIFY CD305

The kinase responsible for the tyrosine phosphorylation of CD305 is not known.

ADDITIONAL INSIGHTS

For further information see Meyaards, L. et al (1997) Immunity &: 283-290.



Database accession numbers
AnimalPIRSWISSPROTEMGBL/GENBANK
 
HumanEntrezgene 3903Q6GTX8
Antibodies

Revised June 25, 2008


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