The skin can be broadly classified into two distinct regions, the epidermis and the dermis. The epidermis is derived from ectoderm and presents as an epithelial layer composed mainly of keratinocytes. Keratinocytes provide skin integrity and produce the stratum corneum, which is the water-impermeable outermost layer of the skin.

LCs are the only DCs that are found in the epidermis during the steady state. LCs are generally found in the basal and suprabasal layers of the epidermis, where they form a dense network of cells that account for approximately 2–4 % of the total epidermal cell population in the epidermis of mice and humans [8]. LCs are the only hematopoietic cells in the epidermis of human skin in the steady state, whereas mice have an additional population: epidermal γδ T cells [9].

LC precursors first populate the epidermis on embryonic day 18 and proliferate in situ to form a radio-resistant, self-renewing population [10, 11]. They are characterized by a unique cytoplasmic organelle known as a Birbeck granule . Although the precise function of Birbeck granules remains unclear, they are thought to play a role in receptor-mediated endocytosis and the transport of cellular materials into the extracellular space [12].

Human and murine LCs are easily identified in the epidermis by the expression of CD45 and major histocompatibility complex (MHC) II molecules. They also constitutively express the lection receptor, namely, langerin/CD207 , which is capable of binding sugar moieties commonly found on a variety of microorganisms [13]. Human and murine LCs express the adhesion molecules E-cadherin and epithelial-cell adhesion molecule (EpCAM) , which anchor LCs to keratinocytes [14, 15], and CD205 that is implicated in antigen capture and antigen processing [16, 17]. Human LCs highly express CD1a, a member of the group 1 CD1 protein, which is capable of presenting microbial lipid antigens to T cells [18] (Table 4.1). Although the majority of LCs are thought to be derived from bone marrow precursors, recent studies have identified a novel pathway by which CD14⁺ cells resident in the dermis acquire LC features following treatment with TGF-β [19, 20]. In humans, CD34⁺ hematopoietic progenitor cells [21, 22], monocytes [23], and dermal CD14⁺ DCs [19] were shown to give rise to LC-like cells in vitro. TGF-β is a critical factor for LC development both in vitro and in vivo, as LCs are absent in the epidermis of TGF-β-deficient mice [14]. LC differentiation may thus be somewhat dependent on the cytokine microenvironment of the skin at any given point in time.

Upon encountering pathogens, LCs can capture antigens and undergo a maturation that involves upregulation of MHC class I and class II molecules—costimulatory molecules including CD40, CD80, and CD86—and chemokine receptors such as CCR7, as well as downregulation of E-cadherin that allows them to migrate out of the skin to draining LNs, where they present antigens to T cells [24]. However, despite intensive studies to reveal the functional role of LCs over the past several decades, the in vivo function of LCs remains not fully understood, as discussed later.

Homeostasis of LCs in the inflamed skin depends on the type and the strength of inflammation. In severe inflammatory conditions, such as ultraviolet (UV) light exposure or cutaneous graft-versus-host disease, LCs are replaced by circulating blood precursors [11, 25]. In contrast, in less severe inflammatory conditions that lead to moderate LC loss, where the epidermal–dermal barrier integrity is preserved and is not accompanied by the release of inflammatory chemokines that recruit blood monocytes, the remaining LCs have the potential to repopulate themselves locally and achieve complete recovery in 1 to 4 weeks after tissue injury. These findings suggest that inflammatory signals may control the dynamics of LC proliferation.

Dermal DCs (dDCs) consist of dermal-resident DCs and migratory LCs on their way to the LNs [28]. Until recently, human and murine dermal-resident DCs were thought to form a homogeneous population that is easily distinguishable from migratory LCs based on the absence of langerin/CD207 expression [13]. However, recent studies have shown that murine langerin-positive dendritic cells in dermis are composed of both LCs and a novel population of dDCs (langerin⁺ dDCs ) [29–31]. The langerin⁺ dDC population represents 10–20 % of the total dDCs pool. In contrast to LCs, langerin⁺ dDCs express the integrin αEβ7 (also called CD103) [32], lack the adhesion molecules E-cadherin and EpCAM, and express low levels of the integrin CD11b. Langerin⁺ dDCs arise from bone marrow precursors in an FMS-like tyrosine kinase 3 (FLT3)-dependent manner [29, 30, 33]. Langerin⁺ dDCs express the same high level of CD24 as LCs, but do not express CX3CR1, F4/80, or signal-regulatory protein alpha (SIRPα), and express low levels of CD11b and EpCAM [33] (Table 4.1).

The classical langerin⁻ dDCs represent the majority (up to 70 %) of the dDC pool and express high levels of the integrin CD11b and several macrophage markers such as F4/80, CX3CR1, and SIRPα [33]. Interestingly, their expression of CD24 is heterogeneous, suggesting that dermal langerin⁻ dDCs might not represent a homogeneous subset of dDCs, either in origin or in maturation status [34].

DCs were thought to be terminally differentiated cells, with no proliferative capacity. However, recent studies have revealed that in lymphoid organs DCs actively proliferate in the steady state [35, 36]. All dermal DC subsets proliferate, although CD103⁺ dDCs do so at a higher rate than the CD11b⁺ subset [33, 34].

The chemokine receptor CCR7 regulates the constitutive migration of all cutaneous DCs to the skin-draining LNs [37, 38]. In the inflammatory state, tissue-resident DC migration to the draining LNs increases markedly [39]. Interestingly, cutaneous DC subsets migrate differently from the skin-draining LNs in response to the sensitization with hapten. Migration of CD11b⁺ and CD103⁺ dDCs reaches a peak 1 day later, followed by LCs at 4 days postsensitization [40, 41]. It is also important to note that cutaneous DCs undergo phenotypic changes upon migration from the skin to the LNs [34].

A newly identified DC subpopulation referred to as TNF-α and inducible NO synthase (iNOS)-producing DC (Tip-DC) has been reported to be critical in bacterial infections, as demonstrated in a model with Listeria monocytogenes [55]. Tip-DCs express CD11c, TNF-α, and iNOS (Table 4.1). Evidence that TNF-α inhibitors were able to reverse disease activity in psoriasis suggests that Tip-DC may represent major inflammatory effector cells in psoriasis [56]. Pathogenicity of Tip-DCs in psoriasis is suggested by the rapid downmodulation of Tip-DC products TNF-α, iNOS, IL-20, and IL-23 during treatment with effective therapies [57, 58]. They have the capacity to skew T cells into Th1 and Th17 T cells, which are a new set of T cells associated with autoimmune inflammation in many disease models [59].

Inflammatory dendritic epidermal cells (IDECs) were found in the epidermis of atopic dermatitis (AD) skin lesions. Compared to LCs, they lack Birbeck granules and langerin expression, but show expression of the mannose receptor (MMR)/CD206, providing IDECs with the ability to take up mannosylated protein antigens [60]. They also express CD1a, CD1b, CD1c, CD11c, CD23, HLA-DR, CD11b, CD206, and the low-affinity receptor for IgE (FcεRII/CD23; Table 4.1). In lesional skin of AD, both IDECs and LCs show expression of the high-affinity receptor for IgE (FcεRI) and CD36; however, expression of both receptors is stronger on IDECs. Peripheral blood monocytes as well as dermal DCs are regarded as potential precursor cells of IDECs [61].