Targeting skin dendritic cells to improve intradermal vaccination

Abstract

Vaccinations in medicine are typically administered into the muscle beneath the skin or into the subcutaneous fat. As a consequence, the vaccine is immunologically processed by antigen-presenting cells of the skin or the muscle. Recent evidence suggests that the clinically seldom used intradermal route is effective and possibly even superior to the conventional subcutaneous or intramuscular route. Several types of professional antigen-presenting cells inhabit the healthy skin. Epidermal Langerhans cells (CD207/langerin(+)), dermal langerin(neg), and dermal langerin(+) dendritic cells (DC) have been described, the latter subset so far only in mouse skin. In human skin langerin(neg) dermal DC can be further classified based on their reciprocal expression of CD1a and CD14. The relative contributions of these subsets to the generation of immunity or tolerance are still unclear. Yet, specializations of these different populations have become apparent. Langerhans cells in human skin appear to be specialized for induction of cytotoxic T lymphocytes; human CD14(+) dermal DC can promote antibody production by B cells. It is currently attempted to rationally devise and improve vaccines by harnessing such specific properties of skin DC. This could be achieved by specifically targeting functionally diverse skin DC subsets. We discuss here advances in our knowledge on the immunological properties of skin DC and strategies to significantly improve the outcome of vaccinations by applying this knowledge.

Fig. 1

In the upper row, LC are visualized within epidermal sheets from murine skin by immunolabeling with anti-langerin antibody (red fluorescence). Dendritic epidermal T cells are identified by anti-CD3 antibodies (green fluorescence). The bottom row demonstrates how well murine LC can be targeted with antibodies injected into the dermis of the ear (anti-langerin, anti-DEC-205, isotype control). Epidermal sheets were prepared 4 days after the injection and stained with a fluorochrome-coupled anti-rat Ig antibody. Note that an unrelated antibody (isotype) does not bind to the LC whereas anti-langerin and anti-DEC-205 antibodies readily find their way into the epidermis and are taken up by LC. The picture to the far right is a higher magnification of DEC-205-targeted LC in situ. Intracellular vesicles containing the targeting antibody can be appreciated

Fig. 2

Human dermal DC obtained by emigration from dermal explants. This means that epidermis and dermis were separated from each other before the onset of culture. Phase contrast photographs of cells that migrated out of the explants into the culture medium over a period of 3 days. Note the typical morphology of mature DC with thin cytoplasmic processes (“veils”), best visible in the two inserts. The processes are motile as can be seen in the bottom row of photographs that were taken about 15 s apart from each other. Please note the shape change of one exemplary “veil” under the white asterisk

Fig. 3

Human skin before (left) and after a 3-day skin explant culture (right). Dermal macrophages were visualized with an immunoperoxidase technique using antibodies against Factor XIIIa, a marker for these cells (Zaba et al. 2007). Positive cells can be identified by the brown reaction product (few examples marked with an asterisk). Note that after 3 days of culture the numbers of dermal macrophages are markedly reduced