CNS myelin induces regulatory functions of DC-SIGN-expressing, antigen-presenting cells via cognate interaction with MOG.

Myelin oligodendrocyte glycoprotein (MOG), a constituent of central nervous system myelin, is an important autoantigen in the neuroinflammatory disease multiple sclerosis (MS). However, its function remains unknown. Here, we show that, in healthy human myelin, MOG is decorated with fucosylated N-glycans that support recognition by the C-type lectin receptor (CLR) DC-specific intercellular adhesion molecule-3-grabbing nonintegrin (DC-SIGN) on microglia and DCs. The interaction of MOG with DC-SIGN in the context of simultaneous TLR4 activation resulted in enhanced IL-10 secretion and decreased T cell proliferation in a DC-SIGN-, glycosylation-, and Raf1-dependent manner. Exposure of oligodendrocytes to proinflammatory factors resulted in the down-regulation of fucosyltransferase expression, reflected by altered glycosylation at the MS lesion site. Indeed, removal of fucose on myelin reduced DC-SIGN-dependent homeostatic control, and resulted in inflammasome activation, increased T cell proliferation, and differentiation toward a Th17-prone phenotype. These data demonstrate a new role for myelin glycosylation in the control of immune homeostasis in the healthy human brain through the MOG-DC-SIGN homeostatic regulatory axis, which is comprised by inflammatory insults that affect glycosylation. This phenomenon should be considered as a basis to restore immune tolerance in MS.

The coming of age of galectins as immunomodulatory agents: impact of these carbohydrate binding proteins in T cell physiology and chronic inflammatory disorders.

Immune cell homoeostasis is attributed to multiple distinct safety valves that are interconnected and intervene at defined checkpoints of the life cycle of immunocytes to guarantee clonal expansion and functional inactivation of self-reactive potentially autoaggressive lymphocytes. Galectins, animal lectins defined by shared consensus amino acid sequence and affinity for beta-galactose containing oligosaccharides, are found on various cells of the immune system, and their expression is associated with the differentiation and activation status of these cells. Over the past few years, galectins have been implicated in the regulation of many aspects of T cell physiology such as cell activation, differentiation, and apoptosis. In addition, a growing body of experimental evidence indicates that galectins may play critical roles in the modulation of chronic inflammatory disorders, autoimmunity, and cancer. Given the increased interest of immunologists in this field, the growing body of information raised during the past few years and the potential use of galectins as novel anti-inflammatory agents or targets for immunosuppressive drugs, we will summarise recent advances on the role of galectins in different aspects of T cell physiology and their impact in the development and/or resolution of chronic inflammatory disorders, autoimmunity, and cancer.

Regulated expression of galectin-1 after in vitro productive infection with herpes simplex virus type 1: implications for T cell apoptosis.

Apoptosis of cytotoxic T lymphocytes by herpes simplex virus type-1 (HSV-1) has been reported to be a relevant mechanism of viral immune evasion. Galectin-1 (Gal-1), an endogenous lectin involved in T-cell apoptosis, has recently gained considerable attention as a novel mechanism of tumor-immune evasion. Here we investigated whether infection of cells with HSV-1 can modulate the expression of Gal-1. Results show that pro-apoptotic Gal-1, but not Gal-3, is remarkably up-regulated in cell cultures infected with HSV-1. In addition, this protein is secreted to the extracellular milieu, where it contributes to apoptosis of activated T cells in a carbohydrate-dependent manner. Since many viruses have evolved mechanisms to counteract the antiviral response raised by the infected host, our results suggest that HSV-1 may use galectin-1 as a weapon to kill activated T cells and evade specific immune responses.

The role of galectins in the initiation, amplification and resolution of the inflammatory response.

Inflammation involves the sequential activation of signalling pathways leading to the production of both pro-inflammatory and anti-inflammatory mediators. Galectins constitute a family of structurally related beta-galactoside-binding proteins, which are defined by their affinity for poly-N-acetyllactosamine-enriched glycoconjugates and sequence similarities in the carbohydrate recognition domain. By crosslinking specific glycoconjugates, different members of the galectin family behave as pro-inflammatory or anti-inflammatory agents, acting at different levels of acute and chronic inflammatory responses. Recent studies highlighted immunomodulatory roles for galectins in vivo in several experimental models of chronic inflammation, suggesting that these carbohydrate-binding proteins may be potential targets for the design of a novel generation of anti-inflammatory agents. In this study, we review recent advances on the role of galectins in the initiation, amplification and resolution of the inflammatory response. In particular, we examine the influence of individual members of this family in regulating cell adhesion, migration, chemotaxis, antigen presentation, immune cell activation and apoptosis. From a better understanding of the molecular basis of galectin-induced immune regulation, we may become able to exploit the potential of these sugar-binding proteins and their glycoligands as suitable therapeutic agents in acute and chronic inflammatory disorders.