Dendritic cell-targeted vaccines

Abstract

Despite significant effort, the development of effective vaccines inducing strong and durable T-cell responses against intracellular pathogens and cancer cells has remained a challenge. The initiation of effector CD8(+) T-cell responses requires the presentation of peptides derived from internalized antigen on class I major histocompatibility complex molecules by dendritic cells (DCs) in a process called cross-presentation. A current strategy to enhance the effectiveness of vaccination is to deliver antigens directly to DCs. This is done via selective targeting of antigen using monoclonal antibodies directed against endocytic receptors on the surface of the DCs. In this review, we will discuss considerations relevant to the design of such vaccines: the existence of DC subsets with specialized functions, the impact of the antigen intracellular trafficking on cross-presentation, and the influence of maturation signals received by DCs on the outcome of the immune response.

Keywords: CD8+ T cells; MHC class I; adjuvants; dendritic cells; immunologic; vaccination.

Figure 1

(A) Human dendritic cell subsets have overlapping functions and phenotypes, but also show some degree of specialization. BDCA1⁺ DCs and BDCA3⁺ DCs both efficiently present antigen on MHCI and MHCII. pDCs can present antigen to CD4⁺ and CD8⁺ T cells, but likely their primary role in the immune response is the production of type I interferon during viral infection. LCs seem to be specialized for cross-presentation on MHCI, while CD14⁺ dermal DCs prime naïve CD4⁺ T cells to generate follicular helper T cells. Inflammatory DCs are monocyte-derived, and are present at sites of inflammation. There is also partial overlap between expression of PRRs among DC subsets. (B) A clear division of labor exists among mouse splenic dendritic cell subsets. CD11b⁻ CD8α⁺ DCs are far superior and essential at priming CD8⁺ T-cell responses, while CD11b⁺ DCs are specialized for presenting antigen on MHCII to stimulate helper T-cell immunity. pDCs can present antigen to CD4⁺ and CD8⁺ T cells, but likely their primary role in the immune response is the production of type I interferon during viral infection like their human counterparts. There is overlap between expression of PRRs among DC subsets, although CD11b⁻ CD8α⁺ DCs express much higher levels of TLR3 while CD11b⁺ DCs uniquely express TLR5 and TLR7 (, , , , , –151).

Figure 2

MHCI cross-presentation pathways of captured antigens. Antigen captured by DCs has different potential fates. Antigens destined for cross-presentation on MHCI have two different intracellular routes. Antigen can be transported from the endocytic vesicles to the cytosol to access the classical MHCI pathway involving proteasomal degradation and transport into the ER or back into the endosomal compartment for loading onto MHCI. The second pathway results in degradation and loading directly in endosomal compartments before peptide–MHCI complexes are transported to the plasma membrane. Modified from Delamarre and Mellman (14).