In situ Delivery of Antigen to DC-SIGN super(+)CD14 super(+) Dermal Dendritic Cells Results in Enhanced CD8 super(+) T-Cell Responses

CD14 super(+) dendritic cells (DCs) present in the dermis of human skin represent a large subset of dermal DCs (dDCs) that are considered macrophage-like cells with poor antigen (cross)-presenting capacity and limited migratory potential to the lymph nodes. CD14 super(+) dDC highly express DC-specific ICAM-3-grabbing non-integrin (DC-SIGN), a receptor containing potent endocytic capacity, facilitating intracellular routing of antigens to major histocompatibility complex I and II (MHC-I andII) loading compartments for the presentation to antigen-specific CD8 super(+) and CD4 super(+) T cells. Here we show using a human skin explant model that the in situ targeting of antigens to DC-SIGN using glycan-modified liposomes enhances the antigen-presenting capacity of CD14 super(+) dDCs. Intradermal vaccination of liposomes modified with the DC-SIGN-targeting glycan Lewis super(X), containing melanoma antigens (MART-1 or Gp100), accumulated in CD14 super(+) dDCs and resulted in enhanced Gp100- or MART-1-specific CD8 super(+) T-cell responses. Simultaneous intradermal injection of the cytokines GM-CSF and IL-4 as adjuvant enhanced the migration of the skin DCs and increased the expression of DC-SIGN on the CD14 super(+) and CD1a super(+) dDCs. These data demonstrate that human CD14 super(+) dDCs exhibit potent cross-presenting capacity when targeted in situ through DC-SIGN.