The Dendritic Cell Dilemma in the Skin: Between Tolerance and Immunity

Abstract

Dendritic cells (DC) are uniquely capable of initiating and directing immune responses. The range of their activities grounds in the heterogeneity of DC subsets and their functional plasticity. Numerical and functional DC changes influence the development and progression of disease, and correction of such dysregulations has the potential to treat disease causally. In this review, we discuss the major advances in our understanding of the regulation of DC lineage formation, differentiation, and function in the skin. We describe the alteration of DC in disease as well as possibilities for therapeutic reprogramming with a focus on tolerogenic DC. Because regulatory T cells (Treg) are indispensable partners of DC in the induction and control of tolerance, we pay special attention to the interactions with these cells. Above all, we would like to arouse fascination for this cell type and its therapeutic potential in skin diseases.

Keywords: DC targeted vaccines; cellular immunotherapy; dendritic cells; interleukin 10; tolerance; treg cells.

Figure 1

Dendritic cells exhibit immunostimulatory or tolerogenic potential depending on the context. DC's fate depends on cytokines and pathogen contact. Inflammatory cytokines and pathogens presenting TLR ligands promote T effector cells, while anti-inflammatory cytokines or interactions with commensal bacterial components produce tolerance, e.g. induce T cell anergy or deletion, or give rise to regulatory T cells.

Figure 2

In vivo targeting of DC for Treg induction. Systemic administration of specifically designed nanoparticles or antibodies combined with antigen delivery for tolerogenic DC targeting in vivo, affects the resulting immune response of allergic and autoimmune diseases in an antigen-specific manner. Epicutaneous application of antigens results in activation of tolerogenic LC in the skin (by dermal patches, Epicutaneous immunotherapy) or tolerogenic DC in skin draining lymph nodes (repetitive exposure to low doses of allergens, Low zone tolerance), respectively, and subsequent control of allergic immune reactions by Treg.

Figure 3

Tolerogenic DC in clinical applications. Ex vivo generation of tolerogenic DC starts with isolation of CD14⁺ monocytic precursor cells from the peripheral blood of the patients. After subsequent in vitro culture in the presence of tolerogenic agents and loading with (auto-) antigens, the tolerogenic DC are re-injected into the patients to affect the inflammatory immune reaction in allergic and autoimmune disorders or in transplantation rejection.