Fucosylated clusterin is a novel DC-SIGN ligand: Its role in HIV transmission and anti-tumor immune response

SABATTE, JUAN

Villa General Belgrano

Congreso; GlycoAr; 2016

Clusterin is a ubiquitous glycoprotein of 75-80 kDa present in almost all tissues and body fluids. It is highly conserved among mammals showing 70-80% identity at the amino acid level. Although clusterin appears to be involved in a variety of physiological and pathological processes such as cell death regulation, complement inhibition, Alzheimer?s disease and cancer progression, its function is still controversial and enigmatic.Clusterin is a highly glycosylated protein being 30 percent of its molecular mass contributed by glycans. The concentration of clusterin in human blood plasma is around 100 g/ml while the concentration in semen is at least 20-fold higher (i.e., 2 to 10 mg/ml), raising the question about the role of semen clusterin in reproduction and sexual transmited diseases. We have reported that semen clusterin bears highly fucosylated Lewis X and Lewis Y type glycans which confer clusterin the ability to bind with high affinity to DC-SIGN, a C-type lectin receptor expressed on the genital mucosa by dendritic cells (DCs) and macrophages. Intriguing, the glycosylation pattern of serum clusterin is different from its semen counterpart, bearing mostly sialylated glycans. Indeed, in contrast with semen clusterin, serum clusterin does not interact with DC-SIGN. We hypothesize that clusterin might play a role in the induction of immune tolerance to paternal antigens required for normal pregnancy. The acquisition of female tolerance against seminal antigens requires the activation of an active tolerogenic response which involves the participation of both, tolerogenic DCs and regulatory T cells (Tregs). In this regard, it has been shown that exposure of the female genital mucosa to seminal plasma triggers the expansion of Tregs in draining lymph nodes. Moreover, we recently reported that seminal plasma induces the differentiation of DCs into a tolerogenic profile. Of note, the induction of a state of tolerance against seminal antigens requires the interaction and endocytosis of seminal antigens by DCs. We have recently shown that fucosylated clusterin promotes the endocytosis of stressed seminal antigens by DCs via DC-SIGN. Supporting that this novel pathway of antigen uptake might be associated to the induction of tolerance rather than immunity, we found that the interaction of semen clusterin with DC-SIGN promotes the ability of DCs to stimulate the expansion of CD25+FOXP3+CD4+ regulatory T cells. Interestingly, the expression of clusterin is up regulated in many types of cancer. Furthermore, fucose containing motifs similar than those found on semen clusterin are ?aberrantly expressed? on different tumors. Recent results from our lab demonstrate that clusterin expressed in different human tumors bears fucosylated motifs and binds to DC-SIGN. We hypothesize that tumoral clusterin, as it semen counterpart, might deliver antigens to DCs via DC-SIGN and modulate DC function, promoting tumor immune escape.