Duality at the gate: Skin dendritic cells as mediators of vaccine immunity and tolerance

Abstract

Since Edward Jenner's discovery that intentional exposure to cowpox could provide lifelong protection from smallpox, vaccinations have been a major focus of medical research. However, while the protective benefits of many vaccines have been successfully translated into the clinic, the cellular and molecular mechanisms that differentiate effective vaccines from sub-optimal ones are not well understood. Dendritic cells (DCs) are the gatekeepers of the immune system, and are ultimately responsible for the generation of adaptive immunity and lifelong protective memory through interactions with T cells. In addition to lymph node and spleen resident DCs, a number of tissue resident DC populations have been identified at barrier tissues, such as the skin, which migrate to the local lymph node (migDC). These populations have unique characteristics, and play a key role in the function of cutaneous vaccinations by shuttling antigen from the vaccination site to the draining lymph node, rapidly capturing freely draining antigens in the lymph node, and providing key stimuli to T cells. However, while migDCs are responsible for the generation of immunity following exposure to certain pathogens and vaccines, recent work has identified a tolerogenic role for migDCs in the steady state as well as during protein immunization. Here, we examine the roles and functions of skin DC populations in the generation of protective immunity, as well as their role as regulators of the immune system.

Keywords: DC targeted vaccines; dendritic cells; immune tolerance; migratory DCs.

Figure 1.

Graphical Schematic of Skin DC Migration to the Cutaneous Lymph Nodes. Epidermal (Langerhans Cells) and dermal skin DC colonize their respective layers of the skin. In both the inflamed and steady state setting, LC and dermal DC enter the lymphatic vessels, before migrating in a CCR7 dependent manner to the local cutaneous draining lymph node bearing either pathogen derived or self antigens. Upon arrival at the lymph node, skin migratory DC enter the paracortical area and present skin derived antigens to T cells. Additionally, post migration, migratory DC can capture and present antigens that have drained freely, such as DEC205 targeted vaccinations. Images were provided by Matthew Woodruff (Wikimedia commons).

Figure 2.

Migratory DC in the Skin and Cutaneous Draining Lymph Node. (A) Murine skin was stained for CD11c (purple), Langerin (green), CD11b (red), and DAPI (blue) in the steady-state. Images were taken at 20 × and are courtesy of Sze-Wah Tse. (B) Proportions of individual migratory DC populations among the total migratory DC subset in the cutaneous draining lymph node in the steady state. Data are adapted from Henri et al. and Mollah et al.