Dendritic cells (DC) provide a bridge between the innate and acquired immune system. HIV exploits the complex pathways of microbial antigen uptake and transport by these cells for initial entry and dissemination. Within DCs, some HIV escapes endolysosomal degradation and antigen presentation pathway to be transferred to CD⁴⁺ lymphocytes during activation of T cell-mediated immunity. In skin DC the C type lectin receptors (CLRs), langerin on Langerhans cells (LC), and DC-SIGN and mannose receptor (MR) on dermal DC subsets are all capable of binding HIV gp120 through its mannose saccharides. Among DCs only the immature DCs in the periphery can bind HIV through CLRs and this enhances HIV fusion with the target cell membrane via CD4/chemokine receptors, or mediates entry into the endolysosomal pathway. Although CLR transfected cell lines and CLR expressing monocyte derived DC (MoDC) can transfer HIV independent of fusion in vitro, observations of DC ex vivo or in vivo show that CLR-enhanced CD4/CCR5-mediated viral fusion appears to be necessary for viral transfer to T cells. Thus HIV utilizes recognition of abundant high mannose glycans on its envelope protein, for binding to CLRs on skin and mucosal DCs, entry via CD4/CCR5 and transport by DCs to CD⁴⁺ lymphocytes in lymph nodes, the major site of viral replication.

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The mannose receptor (MR) is a unique bi-functional molecule with two lectin activities. Its N-terminal cysteine-rich (CR) domain exclusively recognises endogenous acidic glycans, while its C-type-lectin domains (CRDs) bind carbohydrates decorating some microbial surfaces, as well as some secreted endogenous glycoproteins that are cleared through this receptor. In this review we aim to provide an update on some aspects of MR biology with special emphasis on its role in clearance (when expressed in tissue macrophages (Mφ) and sinusoidal endothelia), antigen delivery (as cell associated form on dendritic cells (DCs), or through targeting of its soluble form to lymphoid organs) and cell adhesion (when expressed by lymphatic endothelia).

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Galectins are members of a family of proteins defined by their conserved peptide sequence elements, which are crucial for their affinities to β-galactosides. Unlike other lectins, galectins are cytosolic proteins but can be actively secreted from inflammatory macrophages and can also be passively released when cells expressing galectins are damaged. In recent years, numbers of papers have demonstrated that galectins can act as immunomodulators or proinflammatory factors, implying their roles in immunity against infections. In the initial stage of infection, innate immunity must recognize invasive infections and initiate a defence system efficiently to clear the infection without the aid of acquired immunity. Until recently, discrimination between self and nonself by innate immunity has been considered as the most important element, which can trigger immunity against infections. A novel model, called ‘the Danger model’, has been proposed recently and has since gained much attention and support as the initial recognition mechanism for infection. In the Danger model, innate immunity is more concerned with damage induced by invading pathogens than with the ‘foreignness’ of invading pathogen, immunity is then called into action by alarm signals (danger signals) from injured cells. As galectins can be considered as a new type of proinflammatory factors, secretion and release of which is closely associated with the timing in which the immune system is required to send ‘danger signals’, in this review, the potential roles of galectins as molecules of danger signals will be discussed.

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Several cytokines were described as having carbohydratebinding (lectin) properties. A fine analysis of their high affinity ligands indicated that the specificity is directed against glycans that are generally rare in normal tissues. These lectin activities open new concepts in immunology because it modifies our understanding of their mechanism of action. The carbohydraterecognition domain of the cytokines makes these molecules bifunctional. Consequently, the expression of the biological activity of the cytokine relies on its carbohydrate-binding activity, which allows the specific association of the cytokine receptor with molecular complexes comprising the specific kinase/phosphatase involved in receptor phosphorylation/dephosphorylation and in specific signal transduction. Correlatedly, a cytokine can act only on cells possessing both the receptor and the ligand, the latter being in the case of IL-2 and IL-6 a glycoprotein molecule considered as a receptor. Based on a few examples, it is suggested that molecular modeling of the lower energy conformation of the high affinity ligands of the cytokine and computational docking of these conformers into the 3D-structure of the cytokine are able to propose a localization of the carbohydraterecognition domain.

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