Deepening our understanding of immune sentinels in the skin

Abstract

Advances in our understanding of the skin immune system have a major impact on studies of skin autoimmunity, graft-versus-host disease, inflammation, and cancer as well as on the development of novel vaccines and immunotherapy approaches. In this issue of the JCI, Zaba et al. carefully dissected the complex network of DCs and macrophages residing in normal human skin and defined novel phenotypic markers for these immunocytes (see the related article beginning on page 2517). These studies provide the basis for better insight into the role of important immune sentinels contributing to the maintenance of skin tissue homeostasis and lay the foundation for future studies of the skin immune system.

Figure 1. Normal human skin is characterized by an impressive diversity of immune sentinels.

Skin-based DCs and macrophages sense invading pathogens and serve as sentinels, thereby alerting effectors of the innate and adaptive immune systems to potential danger to the host. Subsets of immune sentinels include CD1a⁺Langerin⁺ LCs located in the epidermis and various subtypes of DCs and macrophages in the dermis. In this issue of the JCI, Zaba et al. (17) used mixed leukocyte assay to identify BDCA-1⁺ DDCs as the major immunostimulatory population in normal human skin. In addition, they found that the mononuclear cells expressing CD163 were less immunostimulatory, but possessed greater phagocytic activity and morphological features of macrophages. These recent morphological, immunophenotypic, and functional findings complement previous studies that defined additional mononuclear subsets including: PDCs, which are relatively rare in normal skin but are capable of producing type I IFNs and express BDCA-2, IL-3 receptor α (IL-3Rα), and CD45RA; CD14⁺ DDCs, which may develop into LCs under the influence of TGF-β; TNF- and iNOS-producing DCs (TIP-DC), characterized by their production of TNF-α and iNOS; and various macrophage subsets. Currently the macrophage population expressing CD68 and CD14 can be further subdivided into classically activated macrophages (M1), developing under the influence of LPS and IFN-γ, and alternatively activated macrophages (M2), developing under the influence of IL-4 and IL-10. The M1 type macrophage expresses CD16, CD32, and CD64, whereas the M2 type macrophage expresses CD163, FXIIIa, MR, and the marker RM3/1 as previously described (15). Circular arrows indicate the self-renewing potential of LCs and DDCs under conditions of tissue homeostasis. Moreover, circulating blood-derived monocytes are potential precursors of LCs, DDCs, and macrophages, especially under inflammatory conditions.

Figure 2. The spectrum of immune sentinels, portrayed in 2 dimensions, reflecting the heterogeneity and flexible functionality of the mononuclear subsets located in normal human dermis.

At one end of the spectrum are DDCs expressing BDCA-1 (also known as CD1c) and DC-SIGN (also known as CD209); at the other end are macrophages expressing CD163. Depending on the skin microenvironment and cellular activation state of the mononuclear cells, additional markers and flexible functionality may emerge between these ends of the spectrum, as reflected by expression of MHC class II antigen (i.e., HLA-DR), CD11c, FXIIIa, MMR (CD206), CD14, and varying degrees of phagocytic activity. At present, the physiological and pathological relevance for the recruitment of and phenotypic as well as functional interactions among these mononuclear cell subsets, not to mention the effector arms of the innate and adaptive immune system in the skin, is not completely understood.