Ligand-specific tuning of CLEC10A signalling strength and dendritic cell responses through engagement of different GalNAc-containing glycan structures

C-type lectin receptors on dendritic cells shape immune responses to pathogens and tumour cells through the specific recognition of glycans. C-type lectin domain family 10 member A [CLEC10A; also known as Macrophage Galactose-type Lectin (MGL)] binds terminal N-acetylgalactosamine (GalNAc) residues, which are often highly exposed on tumours. Signalling through this receptor increases Interleukin-10 (IL-10) and Tumour Necrosis Factor alpha (TNFα) production by monocyte-derived dendritic cells (moDCs), which promotes a T helper 2 (Th2) or type 1 regulatory T-cell (Tr1) response. Recently, several CLEC10A glycan ligands were identified that induce distinct conformational changes in the CLEC10A carbohydrate recognition domain, but their ability to alter moDC function has not been thoroughly explored. Here, we used CLEC10A ligand glycodendrimers to investigate the transcriptional responses induced by the CLEC10A ligands previously modelled and determined how these transcriptional programmes were associated with the cellular moDC responses. The CLEC10A ligand dendrimers varied in their affinity for CLEC10A and their capacity to increase IL-10 produced by moDCs. Although all glycodendrimers induced differential gene expression, this was strongest for the Forssman antigen dendrimer. The gene ontology (GO) terms associated with genes detected across ligands related to mitogen-activated protein kinase (MAPK) signalling, chemotaxis, apoptosis, angiogenesis, cytokine production and CD4+ T-cell differentiation. The CLEC10A ligand dendrimers also altered the chemokine profile secreted by moDCs. Furthermore, these glycodendrimers increased the percentage of C-C Chemokine Receptor type 7 (CCR7)-expressing moDCs, which was prevented by inhibiting CLEC10A signalling. Overall, there was limited evidence for glycan-specific signalling via CLEC10A, but the glycans did alter the magnitude of the CLEC10A-mediated responses.