Extensive repertoire of membrane-bound and soluble dendritic cell-specificICAM-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 es tablishing the initial contact between DCs and resting T cells. DC-SIGN is also a unique type of human immunodeficiency virus-1 (HIV-1) attachment fac tor and promotes efficient infection in trans of cells that express CD4 and chemokine receptors. We have identified another gene, designated here as D C-SIGN2, that exhibits high sequence homology with DC-SIGN. Here we demonst rate 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 mononuc lear cells (PBMCs), and there was cell maturation/activation-induced differ ences in mRNA expression levels. Immunostaining of term placenta with a DC- SIGN1-specific antiserum showed that DC-SIGN1 is expressed on endothelial c ells and CC chemokine receptor 5 (CCR5)-positive macrophage-like cells in t he villi. DC-SIGN2 mRNA expression was high in the placenta and not detecta ble in PBMCs. In DCs, the expression of DC-SIGN2 transcripts was significan tly lower than that of DC-SIGN1. Notably, there was significant inter-indiv idual heterogeneity in the repertoire of DC-SIGN1 and DC-SIGN2 transcripts expressed. The genes for DC-SIGN1, DC-SIGN2, and CD23, another Type II lect in, colocalize to an similar to 85 kilobase pair region on chromosome 19p13 .3, forming a cluster of related genes that undergo highly complex alternat ive splicing events. The molecular diversity of DC-SIGN-1 and -2 is reminis cent of that observed for certain other adhesive cell surface proteins invo lved 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 pathogen esis of HIV-1 infection, as well as for the molecular code required to esta blish complex interactions between antigen-presenting cells and T cells, i. e. the immunological synapse.