Targeting human dendritic cell subsets for improved vaccines

Abstract

Dendritic cells (DCs) were discovered in 1973 by Ralph Steinman as a previously undefined cell type in the mouse spleen and are now recognized as a group of related cell populations that induce and regulate adaptive immune responses. Studies of the past decade show that, both in mice and humans, DCs are composed of subsets that differ in their localization, phenotype, and functions. These progresses in our understanding of DC biology provide a new framework for improving human health. In this review, we discuss human DC subsets in the context of their medical applications, with a particular focus on DC targeting.

Figure 1. Induction of distinct T cell responses by human cutaneous DC subsets

LCs are efficient at inducing high avidity-cytotoxic CD8⁺ T cell and Th2 and Th22 responses. In contrast, CD14⁺ dermal DCs are efficient at inducing antibody-secreting cells (ASC) and T follicular helper (Tfh) cells. Mouse studies demonstrate that activated dermal DCs migrate into the outer paracortex, just beneath the B cell follicles, whereas LCs migrate into the T cell rich inner paracortex [111]. These observations suggest that humoral immunity is preferentially regulated by CD14⁺ dermal DCs, while cellular immunity is preferentially regulated by LCs. GC B: germinal center B cells.

Figure 2. Strategy to modulate the quality of immune responses through DC targeting

DC targeting vaccines constitute anti-DC antibody conjugated with antigens, and potentially with adjuvants. Each component represents a different parameter. First, target antigens on DCs can be strategically selected based on the biology of the DC subsets that one anticipates to deliver antigens. Another consideration is the type of activation signals that the DC molecules may deliver. Second, selection of antigens and their formulation are the key to induce anticipated antigen-specific immune responses. Third, adjuvants can be selected based on the receptors that the target DC subset expresses, and the type of immune responses that one anticipates to induce. Lastly, the localization of the target DCs should be considered to induce T cells homing to the desired sites. Altogether, DC targeting has a potential to selectively induce the desired types of specific immune responses by strategically selecting these parameters.