Design of neo-glycoconjugates that target the mannose receptor and enhance TLR-independent cross-presentation and Th1 polarization

Eur J Immunol. 2011 Apr;41(4):916-25. doi: 10.1002/eji.201040762. Epub 2011 Mar 14.

Abstract

Cross-presentation is an important mechanism by which DCs present exogenous antigens on MHC-I molecules, and activate CD8(+) T cells, cells that are crucial for the elimination of tumors. We investigated the feasibility of exploiting the capacity of the mannose receptor (MR) to improve both cross-presentation of tumor antigens and Th polarization, processes that are pivotal for the anti-tumor potency of cytotoxic T cells. To this end, we selected two glycan ligands of the MR, 3-sulfo-Lewis(A) and tri-GlcNAc (N-acetylglucosamine), to conjugate to the model antigen OVA and assessed in vitro the effect on antigen presentation and Th differentiation. Our results demonstrate that conjugation of either 3-sulfo-Lewis(A) or tri-GlcNAc specifically directs antigen to the MR. Both neo-glycoconjugates showed, even at low doses, improved uptake as compared with native OVA, resulting in enhanced cross-presentation. Using MR(-/-) and MyD88-TRIFF(-/-) bone marrow-derived DCs (BMDCs), we show that the cross-presentation of the neo-glycoconjugates is dependent on MR and independent of TLR-mediated signaling. Whereas proliferation of antigen-specific CD4(+) T cells was unchanged, stimulation with neo-glycoconjugate-loaded DCs enhanced the generation of IFN-γ-producing T cells. We conclude that modification of antigen with either 3-sulfo-Lewis(A) or tri-GlcNAc enhances cross-presentation and permits Th1 skewing, through specific targeting of the MR, which may be beneficial for DC-based vaccination strategies to treat cancer.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CD8-Positive T-Lymphocytes / cytology
  • CD8-Positive T-Lymphocytes / immunology
  • Cell Polarity*
  • Cell Proliferation
  • Cells, Cultured
  • Cross-Priming*
  • Endosomes / immunology
  • Glycoconjugates / immunology*
  • Lectins, C-Type / deficiency
  • Lectins, C-Type / immunology*
  • Lewis Blood Group Antigens
  • Mannose-Binding Lectins / deficiency
  • Mannose-Binding Lectins / immunology*
  • Mice
  • Mice, Inbred C57BL
  • Oligosaccharides / immunology*
  • Receptors, Cell Surface / deficiency
  • Receptors, Cell Surface / immunology*
  • Th1 Cells / cytology
  • Th1 Cells / immunology*
  • Toll-Like Receptors / immunology
  • Trisaccharides / immunology*

Substances

  • Glycoconjugates
  • Lectins, C-Type
  • Lewis Blood Group Antigens
  • Mannose-Binding Lectins
  • Oligosaccharides
  • Receptors, Cell Surface
  • Toll-Like Receptors
  • Trisaccharides
  • mannose receptor
  • sulfo-Lewis(a)
  • N,N',N''-triacetylchitotriose