Extensive repertoire of membrane-bound and soluble dendritic cell-specific ICAM-3-grabbing nonintegrin 1 (DC-SIGN1) and DC-SIGN2 isoforms. Inter-individual variation in expression of DC-SIGN transcripts.
Expression in dendritic cells (DCs) of DC-SIGN, a type II membrane protein with a C-type lectin ectodomain, is thought to play an important role in establishing the initial contact between DCs and resting T cells. DC-SIGN is also a unique type of human immunodeficiency virus-1 (HIV-1) attachment factor and promotes efficient infection in trans of cells that express CD4 and chemokine receptors. We have identified another gene, designated here as DC-SIGN2, that exhibits high sequence homology with DC-SIGN. Here we demonstrate that alternative splicing of DC-SIGN1 (original version) and DC-SIGN2 pre-mRNA generates a large repertoire of DC-SIGN-like transcripts that are predicted to encode membrane-associated and soluble isoforms. The range of DC-SIGN1 mRNA expression was significantly broader than previously reported and included THP-1 monocytic cells, placenta, and peripheral blood mononuclear cells (PBMCs), and there was cell maturation/activation-induced differences in mRNA expression levels. Immunostaining of term placenta with a DC-SIGN1-specific antiserum showed that DC-SIGN1 is expressed on endothelial cells and CC chemokine receptor 5 (CCR5)-positive macrophage-like cells in the villi. DC-SIGN2 mRNA expression was high in the placenta and not detectable in PBMCs. In DCs, the expression of DC-SIGN2 transcripts was significantly lower than that of DC-SIGN1. Notably, there was significant inter-individual heterogeneity in the repertoire of DC-SIGN1 and DC-SIGN2 transcripts expressed. The genes for DC-SIGN1, DC-SIGN2, and CD23, another Type II lectin, colocalize to an approximately 85 kilobase pair region on chromosome 19p13.3, forming a cluster of related genes that undergo highly complex alternative splicing events. The molecular diversity of DC-SIGN-1 and -2 is reminiscent of that observed for certain other adhesive cell surface proteins involved in cell-cell connectivity. The generation of this large collection of polymorphic cell surface and soluble variants that exhibit inter-individual variation in expression levels has important implications for the pathogenesis of HIV-1 infection, as well as for the molecular code required to establish complex interactions between antigen-presenting cells and T cells, i.e. the immunological synapse.
Mummidi
S
S
South Texas Veterans Health Care System, Audie L. Murphy Division, San Antonio, Texas 78229-4404, USA.
Catano
G
G
Lam
L
L
Hoefle
A
A
Telles
V
V
Begum
K
K
Jimenez
F
F
Ahuja
S S
SS
Ahuja
S K
SK
D000328:Adult; D000595:Amino Acid Sequence; D015703:Antigens, CD / Q000097:blood; D018952:Antigens, CD34 / Q000097:blood; D000943:Antigens, Differentiation; D001483:Base Sequence; D001665:Binding Sites; D015815:Cell Adhesion Molecules / Q000378:metabolism*; D002454:Cell Differentiation; D002460:Cell Line; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology*; D004730:Endothelium, Vascular / Q000166:cytology / Q000276:immunology; D005091:Exons; D005260:Female; D014644:Genetic Variation; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000276:immunology*; D006801:Humans; D037102:Lectins / Q000737:chemistry / Q000235:genetics* / Q000276:immunology*; D037181:Lectins, C-Type; D008264:Macrophages / Q000166:cytology / Q000276:immunology; D008969:Molecular Sequence Data; D010920:Placenta / Q000166:cytology / Q000276:immunology; D011247:Pregnancy; D014176:Protein Biosynthesis; D020033:Protein Isoforms / Q000737:chemistry / Q000235:genetics / Q000276:immunology; D012333:RNA, Messenger / Q000235:genetics; D011956:Receptors, Cell Surface / Q000737:chemistry / Q000235:genetics* / Q000276:immunology*; D011994:Recombinant Proteins / Q000737:chemistry / Q000276:immunology; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D014158:Transcription, Genetic; D014162:Transfection; D000099215:DC-Specific ICAM-3 Grabbing Nonintegrin
D015703:Antigens, CD; D018952:Antigens, CD34; D000943:Antigens, Differentiation; D015815:Cell Adhesion Molecules; D037102:Lectins; D037181:Lectins, C-Type; D020033:Protein Isoforms; D012333:RNA, Messenger; D011956:Receptors, Cell Surface; D011994:Recombinant Proteins; D000099215:DC-Specific ICAM-3 Grabbing Nonintegrin; C483616:ICAM3 protein, human