|Fig. 1. DC present in mucosal tissues at sites of HIV-1 exposure express DC-SIGN. HIV-1 can bind DC-SIGN and thus be transported to its target, the CD4+T cell, via DC migration to lymph nodes. DC-SIGN-ICAM-3 interaction enhances trans HIV-1 infection of T cells.|
The mechanism(s) through which dendritic cells (DC) are involved in the immune response have not been well characterized. Under normal circumstances, DC capture antigen and process it internally to form MHC-peptide complexes. Following antigen uptake, DC may migrate from the periphery to lymph nodes, where they can present MHC-peptide complexes to resting T cells. This initial contact between DC and resting T cells is proposed to occur via a dendritic cell-specific, ICAM-3 grabbing non-integrin (DC-SIGN)-ICAM-3 interaction. DC-SIGN was originally discovered as a C-type lectin capable of binding the HIV-1 envelope glycoprotein gp1201 and has since been shown to be important for supporting primary immune responses2 and enhancing HIV infection of T cells.3,4 The restricted expression of DC-SIGN on DC highlights two of DC contrasting functions: initiation of immunostimulatory responses and promotion of the binding and transmission of HIV-1 to T cells.2,3,5
Geijtenbeek et al. have demonstrated that DC-SIGN is exclusively expressed by DC, mediates adhesion between DC and resting T cells via ICAM-3, is involved in DC-T cell clustering, and is required for DC-induced proliferation of resting T cells.2 It is a 404 amino acid (aa), 44 kDa protein composed of three distinct domains: an N-terminal cytoplasmic domain, seven complete (and one incomplete) tandem repeats of nearly identical sequence, and an extracellular C-terminal region that is homologous to calcium-dependent lectins. Antibodies against beta 2 integrins (e.g. LFA-1 and aD beta 2), known receptors for ICAM-3, do not significantly block binding of DC to ICAM-3 indicating that this interaction is integrin-independent. DC-ICAM-3 binding, however, is calcium-dependent. DC form clusters with ICAM-3 transfected K562 cells in a DC-SIGN-dependent fashion since anti-DC-SIGN antibodies can effectively block this interaction. Clustering appears transient, indicating that DC-SIGN-ICAM-3 interactions are actively regulated. Antibodies to DC-SIGN also show that DC-SIGN-mediated interactions are important in the primary immune response.
DC-SIGN also plays a role in HIV-1 infection as a DC-specific HIV-1 binding protein and it enhances HIV-1 infection of T cells.3,4 DC-SIGN does not act as a receptor that permits HIV-1 entry similar to the CD4-CCR5 complex. It does not mediate HIV-1 entry, instead DC-SIGN captures HIV-1 and facilitates infection of HIV-1 permissive cells in trans. The HIV-1 virus can exploit DC migration by binding DC-SIGN on the surface of immature DC via gp120, thus hitch-hiking to its target, the CD4+ T cell (see Figure 1). DC-SIGN then binds ICAM-3 on the surface of the CD4+ T cell thus bringing the HIV-1 virus in close proximity to the T cell facilitating cell entry via CD4 and CCR5 interaction. DC-SIGN is present at sites of first exposure to HIV-1, including mucosal tissues of the cervix, rectum and uterus in regions beneath the stratified squamous epithelium in the lamina propria. Importantly, DC-SIGN-bound HIV-1 retains infectivity after long-term culture. Binding of the HIV-1 virus to DC-SIGN appears to stabilize the molecule, allowing it to maintain its infectivity for up to four days.
These functions of DC-SIGN illustrate the importance of DC within the immune system. DC-SIGN may facilitate DC interaction with naïve T cells in order to develop immunity. It can also facilitate DC interaction with T cells and promote HIV-1 infection. Questions still remain, however, as to how DC-SIGN functions in vivo and what other possible roles DC-SIGN may play. For example, what other pathogens may be transmitted via DC-SIGN expression on DC? Will the elucidation of the DC-SIGN transporter mechanism open doors for a vaccine to fight HIV-1? A closely related gene, DC-SIGNR, was recently reported and may indicate the formation of possible DC-SIGN/DC-SIGNR hetero-oligomers.6 Further studies on the expression and function of these two variants are necessary.