Antigen-presenting cell subset specific targeting has immunological consequences

Antigen-presenting cells (APCs) represent a heterogeneous population characterized by their functional specialization. Consequently, targeting specific APC-subsets offers opportunities to induce particular immune responses. To validate this, we targeted lentivectors (LVs) specifically to APC-subsets using the nanobody (Nb) display technology. This approach enables pseudotyping of LVs by combining a binding-defective but fusogenic form of VSV.G with a membrane-bound APC-specific Nb. Three Nbs were selected: DC1.8, R3_13 and DC2.1. The respective LVs are referred to as DC1.8-, R3_13- and DC2.1-LVs. Flow cytometry performed on cells obtained from in vivo transduced murine or ex vivo transduced human lymph node cells demonstrated that DC1.8-LVs and R3_13-LVs specifically transduced murine and human myeloid dendritic cells (DCs) respectively. In contrast, DC2.1-LVs transduced both human and murine macrophages, plasmacytoid and myeloid DCs. Next we examined the immune response elicited by intranodal immunization of mice with ovalbumin (OVA) encoding DC1.8- or DC2.1- LVs. DC2.1-LVs outperformed DC1.8-LVs in expansion of functional OVA-specific CD8 T cells. Whereas the expansion of CD4 T cells was comparable upon DC1.8- and DC2.1-LV immunization, the cytokine profile of these CD4 T cells revealed that DC1.8-LVs primarily induced the secretion of IL-17 and IFN-c while DC2.1- LVs primarily induced the production of IFN-c and IL-2. This difference in CD4 and CD8 T cell response was reflected in therapy, demonstrating lower efficacy of DC1.8-LVs when compared to DC2.1-LVs. In conclusion, these findings open the perspective of a vaccination strategy that induces very particular immune responses by targeting a specific DC-subset hence enables full exploitation of the immune system.