Deepening our understanding of immune sentinels in the skin (original) (raw)
In a study reported in this issue of the JCI, Zaba et al. (17) shed new light on the phenotype and function of DDCs and macrophages. Using a panel of monoclonal antibodies to carefully dissect the phenotypic expression profile of DDCs and macrophages, they found 2 major subpopulations of dermal immune sentinels. An overview of the mononuclear cell subsets located in the epidermis and dermis of normal human skin incorporating the findings of Zaba et al. is portrayed in Figure 1. The BDCA-1+CD11c+HLA-DR+ DDCs possessed strong stimulatory capacity for allogeneic T cells, and a second macrophage-like population expressed CD163 and factor XIIIa (FXIIIa). CD163 is a hemoglobin/haptoglobin complex–binding macrophage scavenger receptor expressed on the majority of tissue macrophages (18) and can be readily added to the phenotypic criteria for skin macrophages. FXIIIa, best known for its role in coagulation, is also a tissue transglutaminase with a potential functional role in wound healing and other cutaneous disorders (4). Expression of FXIIIa is related to cell activation and inducible via IL-4 in alternatively activated macrophages (19). FXIIIa is also expressed in migratory DDCs (6, 11), monocyte-derived DCs (20), hematopoietic progenitor cell–derived DDC equivalents (21), and a population of MHC class II+ dendritic-appearing cells of the dermis termed “dermal dendrocytes” (22). Despite these new findings, an immediate question arises: What is the biological significance of FXIIIa expression by dermal macrophages and DCs? Rather than being a lineage-specific marker, accumulating data suggest that FXIIIa expression indicates an alternative cellular activation state induced by exposure of DCs and macrophages to IL-4 (19, 20). Furthermore, FXIIIa expression might indicate a potential functional role in tissue remodeling. Thus, the original description of FXIIIa dermal dendrocytes in various pathological states (22) might have included both DCs and macrophages with a dendritic morphology residing in a distinctive cytokine-containing (e.g., IL-4–rich) skin microenvironment.
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.
Accumulating data seem to indicate that there exists a continuum of phenotypes and functions and remarkable plasticity between tissue-resident DCs and macrophages (23). Based on the findings by Zaba et al. (17), it is clear that certain phenotypic markers may be useful to define mononuclear cell subsets at each end of a spectrum. For example, BDCA-1+ cells identify DDCs with potent allostimulating properties, while the CD163+ cells lacked significant allostimulatory capacity but possessed greater phagocytic activity. As portrayed in Figure 2, between these ends of the spectrum, there are dermal mononuclear cell subsets that express various markers that may identify cell types with more flexible functionality as regards antigen presentation and phagocytosis. Thus, it is now well established that immature DCs, including DDCs, can be phagocytic, a cellular function usually attributed to macrophages (24, 25). On the other hand, macrophages might be potent antigen-presenting cells for CD8+ T cells (26). Expression of CD1a on DDCs indicates potent antigen-presenting function, while expression of CD14 indicates a precursor role for LCs (11). Thus, tissue-resident mononuclear sentinels of the dermis are likely to exist in a pluripotent state and, depending on microenvironmental factors, may acquire an antigen-presenting mode, migratory mode, or tissue-resident phagocytic mode.
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.