Mononuclear Phagocytes of the Skin
Sena J. Lee
András Schaffer
INTRODUCTION
The mononuclear phagocyte system (MPS) is composed of at least three subsets of tissue histiocytes including monocytes, macrophages, and dendritic cells (DCs) that have crucial roles in maintaining tissue homeostasis. Its ubiquitous tissue distribution and enrichment in lymphoid organs and barrier sites, such as skin, allow its participation in diverse activities relevant in infection, inflammation, autoimmunity, tissue regeneration, cancer, and organ transplantation. Langerhans cells (LCs) situated within the epidermis and hair follicles were originally considered to be the main component of the cutaneous MPS. However, accumulating data show that the dermis and subcutaneous fat contain a dense network of DCs and macrophages as well. In this chapter, we will review the diverse subsets of cutaneous MPS including LCs, steady-state dermal DCs (DDCs), monocyte-derived inflammatory DCs, plasmacytoid DCs as well as various functional macrophage subsets. We will summarize how immunophenotypes and transcriptional regulatory programs differentiate among MPS subsets and how these cells contribute to cutaneous inflammatory, infectious, and neoplastic processes (Figs. 4-1 and 4-2).
 FIGURE 4-1. Dendritic cell subtypes in normal (A) and inflamed skin (B). Immunophenotype, postulated function, and associated cutaneous disorders are illustrated. ACD, allergic contact dermatitis; AD, atopic dermatitis; DC, dendritic cell; DDC, dermal dendritic cell; LC, Langerhans cell; TH, T helper; TFH, follicular T helper cells; Treg, regulatory T cells; Tip-DC, TNF-α- and iNOS-producing dendritic cell; pDC, plasmacytoid dendritic cell; BPDCN, blastic plasmacytoid dendritic cell neoplasm; IFN, interferon; GVHD, graft-versus-host disease. |
 FIGURE 4-2. Macrophage subtypes in the skin. Transcriptional master regulators, signature cytokines, postulated function, and associated cutaneous disorders are illustrated. TH, T helper. |
DENDRITIC CELL SUBSETS IN NORMAL SKIN
DCs are professional phagocytes that control most adaptive immune responses. They are superior to macrophages and monocytes in their antigen presentation and migratory and naïve T-cell priming properties. DCs are also distinguished by their dendritic morphology and high level of co-stimulatory molecules accompanying major histocompatibility complex (MHC) class II expression. Steady-state skin hosts distinct functional and phenotypic DC subsets that are microanatomically compartmentalized. LCs uniquely reside within the epidermis, while the dermis harbors three DC populations: CD141 (BDCA-3)+ dermal dendritic cells (DDCs), CD14+ DDC, and CD1c (BDCA-1)+ DDCs. (Fig. 4.1A).
Langerhans Cells
LCs are localized in the epidermis, where they continuously sample and transport antigens to draining lymph nodes. They can be identified on the basis of the expression of CD1a, S-100, CD11c, CD207/Langerin, E-cadherin, and HLA-DR. Tissue-resident LCs in mice, and likely in humans, are thought to arise from nonmonocytic embryonic precursors that seed the skin prior to birth.1,2 They also possess local proliferative potential that might contribute to the maintenance of steady-state LCs.3,4
A unique feature of epidermal LCs is the presence of Birbeck granules (BGs). Electron microscopy reveals BGs as cytoplasmic granules that display a hemispherical bleb at one end of a linear rodlike structure, often likened to that of a tennis racquet. The formation of BGs is organized by CD207/Langerin, a mannose-binding lectin. Mutation in Langerin causes lack of BGs in LCs.5 The function of BGs is still not completely understood, although most studies point toward an active role in receptor-mediated endocytosis and participation in the antigen-processing and presenting function of LCs.
Under inflammatory conditions, epidermal LCs expand by the recruitment and differentiation of circulating monocytes. Hair follicles play a critical role in this recruitment. Hair follicle keratinocytes produce CCL2 in the infundibulum and CCL20 in the isthmus, which are signals for the CCR2- and CCR6-dependent recruitment of LC precursors to the follicle and epidermis.6 Destruction of hair follicle portals for LC recruitment such as seen in lichen planopilaris results in a decrease of epidermal LCs.6 Reduction in the number of LCs has also been observed in nutritional dermatitis, likely due to zinc deficiency–induced apoptosis.7
The role of LCs in inflammatory dermatoses is diverse. LCs are the most potent human DC subtype for the induction of primary cytotoxic CD8+ T-cell responses.8 Nonetheless, their role in graft-versus-host disease, a prototypical cytotoxic T-cell response, is not clearly established.9,10 In addition, LCs can initiate the differentiation of11 tissue-resident memory T cells toward TH1, TH2, TH17, and TH22 phenotypes. Impaired LC function has been observed in atopic dermatitis (AD), a TH2-driven disease, while defective LC migration has been demonstrated in psoriasis, a TH1- and TH17-skewed inflammatory condition.12,13 In contrast, in allergic contact dermatitis, LCs are thought to promote tolerance by anergizing CD8+ T cells and activating regulatory T (Treg) cells.14,15
CD141 (BDCA-3)+ Dermal Dendritic Cells
CD141 (BDCA-3)+ DDCs are located in superficial perivascular spaces and express Toll-like receptor 3 (TLR-3). They express low levels of CD11c and CD1c and skin-related myeloid markers such as factor XIIIa and CD163. They lack CD1a, CD103, or C-type lectin receptors such as CD209 (DC-SIGN), CD205 (DEC205), and CD207 (Langerin).16 Because they express low levels of CD80 and CD86 costimulatory molecules, they are poor inducers of naïve T-cell proliferation. As the major IL-10-producing skin-resident DC subset in the skin, they induce T-cell hyporesponsiveness and CD25high Foxp3+ regulatory T cells that dampen skin inflammation.16
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