Functional Specialization of Skin Dendritic Cell Subsets in Regulating T Cell Responses

Abstract

Dendritic cells (DC) are a heterogeneous family of professional antigen-presenting cells classically recognized as most potent inducers of adaptive immune responses. In this respect, Langerhans cells have long been considered to be prototypic immunogenic DC in the skin. More recently this view has considerably changed. The generation of in vivo cell ablation and lineage tracing models revealed the complexity of the skin DC network and, in particular, established the existence of a number of phenotypically distinct Langerin(+) and negative DC populations in the dermis. Moreover, by now we appreciate that DC also exert important regulatory functions and are required for the maintenance of tolerance toward harmless foreign and self-antigens. This review summarizes our current understanding of the skin-resident DC system in the mouse and discusses emerging concepts on the functional specialization of the different skin DC subsets in regulating T cell responses. Special consideration is given to antigen cross-presentation as well as immune reactions toward contact sensitizers, cutaneous pathogens, and tumors. These studies form the basis for the manipulation of the human counterparts of the murine DC subsets to promote immunity or tolerance for the treatment of human disease.

Keywords: Langerhans cells; Langerin; contact hypersensitivity; cross-presentation; dendritic cells; immunotherapy; infectious skin disease; skin cancer.

Figure 1

The Langerhans cell paradigm: Ralph Steinman’s scheme of key dendritic cell functions. DC, including epidermal LC, exist in two phenotypically and functionally distinct states: as immature cells highly specialized in antigen uptake and processing and as mature cells committed to antigen presentation that activate or tolerize naïve T cells. The two functional programs are connected by DC migration from peripheral tissues to draining LN, which is essential for naïve T cells to encounter their cognate antigen.

Figure 2

Langerhans cells: sentinels of the skin. (A) LC network visualized in an epidermal sheet of mouse ear skin with MHC-II antibody staining (green fluorescence) (37). Photograph by courtesy of Julia Ober-Blöbaum and Björn Clausen. (B) Scanning electron microscopy of a LC sitting on a keratinocyte (38). Photograph by courtesy of Kristian Pfaller and Patrizia Stoitzner.

Figure 3

Skin dendritic cell subsets in mice. Scanning electron microscopy picture of a skin section depicting several layers of keratinocytes and the collagen meshwork of the dermis (38). Photograph by courtesy of Kristian Pfaller and Patrizia Stoitzner. Phenotypically distinct murine skin-resident DC subsets are depicted, including the most commonly used markers for their identification. The color code matches the human counterparts shown in Figure 4.

Figure 4

Dendritic cell subsets in human skin. Scanning electron microscopy picture of a section through the skin depicting several layers of keratinocytes and the collagen meshwork of the dermis (38). Photograph by courtesy of Kristian Pfaller and Patrizia Stoitzner. Phenotypically distinct human skin-resident DC subsets are described by their most prominent markers. The color code represents the murine counterparts shown in Figure 3.