Harnessing human dendritic cell subsets to design novel vaccines

Abstract

Dendritic cells (DCs) orchestrate a repertoire of immune responses that endow resistance to infection and tolerance to self. DC plasticity and subsets are prominent determinants of the quality of elicited immune responses. Different DC subsets display different receptors and surface molecules and express different sets of cytokines/chemokines, all of which lead to distinct immunological outcomes. Recent findings on human DC subsets and their functional specialization have provided insights for the design of novel human vaccines.

Figure 1. Human skin mDC subsets

Epidermal- and dermal-resident DCs were allowed to migrate from their respective tissues and were harvested after 2 days. The cells were enriched with a Ficoll-diatrizoate gradient, stained with CD1a and CD14 mAbs and analyzed by flow cytometry. Epidermal sheets yielded CD1a^hiCD14⁻ cells. Dermis yielded two distinct populations: CD1a⁻CD14⁺ cells (dermal CD14⁺ DCs) and CD1a^dimCD14⁻ cells (dermal CD1a⁺ DCs).

Figure 2. Skin DC subsets different sets of cytokines

Isolated skin DC subsets were stimulated with CD40L for 24 h, and the secreted cytokine/chemokines were measured.

Figure 3. IL-12, a key cytokine for the development of human humoral responses

When DCs form the “ménage à trois” complex with T cells and B cells, IL-12 derived from activated DCs directly acts on naïve B cells to induce their differentiation into plasma cells, while IL-12 from DCs also induces CD4⁺ T cells to secrete IL-21 that promotes plasma cell differentiation.

Figure 4. Understanding human myeloid dendritic cell subsets for the rational design of novel DC-targeting vaccines

Novel vaccines that will prevent and treat chronic diseases such as HIV rely on rational immunological approaches and aim at activating both the cellular and the humoral arm. We envision that targeting antigens and activation of distinct mDC subsets, with different specializations, will result in the generation of a broad and long lived immune protection. Thus, the most efficient vaccines might be those that will target both LCs and dermal CD14⁺ DCs thereby allowing the maximal stimulation of cellular and humoral immune responses and the generation of long-term memory protection.