Glycosidic Tn-based vaccines targeting dermal dendritic cells favor germinal center B-cell development and potent antibody response in the absence of adjuvant

Abstract

In vivo targeting of C-type lectin receptors is an effective strategy for increasing antigen uptake and presentation by den-dritic cells (DCs). To induce efficient immune response, glycosylated tumor-associated Tn antigens were used to target DCs through binding to macrophage galactose-type lectin (MGL). The capacity of Tn-glycosylated antigens-and the multiple antigenic glycopeptide Tn3 therapeutic candidate vaccine-to target mouse and human MGL DCs are demonstrated, especially regarding dermal DCs. In mice, MGL CD103 dermal DCs efficiently captured and processed glycosylated Tn an-tigen in vivo, inducing a potent major histocompatibility complex (MHC) class II-restricted T-cell response. Intradermal immunization with Tn-glycopeptides induced high levels of Th2 cytokines-even in the presence of unmethylated cytosine-phosphate-guanosine-and was associated with increased expansion of the germinal center B-cell population. Therefore, MGL acts as an efficient endo-cytic antigen receptor on dermal DCs in vivo, able to prime Tn-specific T-and B-cell responses. Moreover, even in the absence of adjuvant, immunization with this glycosidic Tn-based vaccine induced high levels of anti-Tn antibody responses, recognizing human tumor cells. In vivo DC-targeting strategies, based on Tn-MGL interactions, constitute a promising strategy for enhancing anti-gen presentation and inducing potent antibody response. (Blood. 2010;116(18): 3526-3536)

Targeting of macrophage galactose‐type C‐type lectin (MGL) induces DC signaling and activation

“…The targeting of MGL expressed by dermal DCs induced a strong HLA class II-restricted T-cell response with a concomitant induction of a potent anti-Tn antibody response following the internalization of MAG:Tn3 glycoimmunogen, containing a viral CD4 + T-cell epitope [29]. Moreover, MGL enhanced both CD4 + and CD8 + -T lymphocyte activity in TLR independent manner when interacted with Tn-OVA (ovalbumin) antigen [30].…”

Tn Glycosylation of the MUC6 Protein Modulates Its Immunogenicity and Promotes the Induction of Th17-biased T Cell Responses

“…MGL is a type II transmembrane protein that recognizes terminal GalNAc residues in a calcium-dependent manner (34) and displays a remarkable specificity for the Tn antigen, being able to mediate GalNAcantigen uptake and presentation by dendritic cells (35,65). Our results showing inhibition of internalization by dendritic cells of MUC6:Tn(T1) with EDTA and with MGL-specific antibody strongly suggest that this lectin could mediate the MUC6:Tn glycoprotein entry to dendritic cells at low doses.…”

“…Several MUC6 33-47 -specific IA b -restricted T cell hybridomas were selected on the basis of their specific IL-2 secretion following in vitro stimulation by this peptide. Representative results are shown for hybridomas IG7 and IG11, which showed dose-dependent responses to the MUC6 [33][34][35][36][37][38][39][40][41][42][43][44][45][46][47] presented by IA b -transfected fibroblasts (Fig. 6A).…”

“…In particular, we and others have recently demonstrated that the macrophage Gal/ GalNAc lectin (MGL) specifically recognizes the Tn antigen (34) and mediates enhanced presentation of Tn-glycosylated peptides (35). We thus next evaluated binding and internalization of Alexa 647-labeled MUC6:Tn(T1) by BMDC.…”

“…Three peptides, MUC6 [33][34][35][36][37][38][39][40][41][42][43][44][45][46][47] , MUC6 83-97 , and to a lesser level, MUC6 98 -112, stimulated specific responses of these LN cells (Fig. 4B).…”