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Immune Surveillance in the Skin: Mechanisms and Clinical Consequences

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Immune Surveillance in the Skin: Mechanisms and Clinical Consequences REVIEWS IMMUNE SURVEILLANCE IN THE SKIN: MECHANISMS AND CLINICAL CONSEQUENCES Thomas S. Kupper and Robert C. Fuhlbrigge The skin, as the primary interface between the body and the environment, provides the first line of defence against a broad array of microbial pathogens and trauma. In addition to its properties as a physical barrier, the skin has many active defence mechanisms. In this review, we discuss the interaction between the innate and adaptive immune systems in the skin as a model for immune function at epithelial-cell interfaces with the environment. How these mechanisms account for the robust nature of cutaneous immune surveillance and how their dysregulation drives the pathogenesis of inflammatory skin disorders and skin-based tumours are the subjects of this review. We live in a hostile environment, surrounded by micro- misdirected immune activity is implicated in the patho- bial pathogens and subject to a range of physical and genesis of a large variety of acquired inflammatory skin chemical insults. To survive in this environment, verte- disorders, including psoriasis, atopic and allergic contact brates have evolved complex immune systems. A key dermatitis, lichen planus, alopecia areata and vitiligo4–10. element of this defence is the deployment of rapid The role of immune dysfunction in these conditions is response elements at the most probable sites of attack, emphasized by their response to immunosuppressive which are the epithelial-cell boundaries between the therapeutic interventions11–14. body and the environment in the skin, gut and lungs. Understanding the mechanisms of immune surveil- As the body’s largest and most exposed interface with lance in the skin and tissue-specific immune responses the environment, the skin has a central role in host also has important implications for the rational design defence. Before the relatively recent discovery of the of vaccines. To promote protective immunity, an immunological defences of skin, the cutaneous interface immunization protocol must elicit not only an antigen- was viewed as a passive barrier between the host and the specific immune response, but also an effective memory hostile environment. In the past few decades, however, it response that will provide long-lived protection at the has become apparent that the mechanical aspects of epi- most probable sites of invasion. This applies equally to dermal defence are reinforced by a versatile and robust immunization against infectious organisms, which in system of immune surveillance1 (FIG. 1).The crucial role most cases invade through the skin or the epithelia of Department of Dermatology, of immune surveillance in maintaining homeostasis is the gastrointestinal or respiratory systems, and to the Brigham and Women’s Hospital, Harvard Institutes evident from the marked increase in the frequency and elicitation of immune responses against tumours. As we of Medicine, 77 Avenue severity of cutaneous malignancies and infections when discuss, the route and means of adjuvant stimulation Louis Pasteur, Boston, immune function is limited, for example in patients with that is used can affect the effectiveness and utility of Massachusetts 02115, USA. genetic and acquired immunodeficiency disorders and specific vaccine strategies. Correspondence to R.C.F. in those receiving immunosuppressive therapy after In this review, we discuss these issues in the context e-mail: rfuhlbrigge@ 2,3 partners.org organ transplantation .The regulation of skin of recent advances in our understanding of cutaneous doi:10.1038/nri1310 defence mechanisms is also crucial, as inappropriate or immune mechanisms, highlighting the interaction of NATURE REVIEWS | IMMUNOLOGY VOLUME 4 | MARCH 2004 | 211 © 2004 Nature Publishing Group REVIEWS innate and adaptive immune systems in the induc- cells (DCs) and macrophages, provide an early warning tion and maintenance of effective cutaneous immune system by releasing stored and inducible ANTIMICROBIAL surveillance. PEPTIDES,chemotactic proteins and cytokines15–19 (FIG. 2). Keratinocyes are important and often under-appreciated Innate immune surveillance participants in cutaneous immune responses. They Central to our model of cutaneous immune surveil- produce large quantities of interleukin-1α (IL-1α), lance are the cells resident in the skin, which function tumour-necrosis factor (TNF) and antimicrobial pep- as sentinels for DANGER SIGNALS, including invasion by tides such as β-defensins in response to various stim- microorganisms. Keratinocytes and LANGERHANS CELLS in uli, including kinetic and thermal trauma, ultraviolet the epidermis, as well as dermal mast cells, dendritic radiation, cytokines and neuropeptides15,20–22.IL-1α (and IL-1β from epidermal Langerhans cells), in turn, acts as a potent stimulator of local immune function23. Keratinocytes also produce a large number of Keratinocyte Langerhans cell chemokines and other immunoregulatory cytokines in response to stimulation16,24–27.These products have vari- ous important effects on resident innate immune cells in the skin, such as mast cells, DCs and macrophages, resulting in the upregulation of expression of other inducible mediators and recruitment of additional immune cells from the blood28.The induction of local Epidermis inflammation through IL-1, however, depends on the balance of agonists (IL-1α,IL-1β, caspase-1 and IL-1 CLA receptor 1; IL-1R1) and antagonists (IL-1Ra and IL-1R2) Dermal fibroblast that are active in this pathway15,16,23.Each of these mole- cules can be produced by keratinocytes under various Memory T cell conditions, as well as by other cells that are resident in the skin, making it difficult to predict the effects of specific interventions. New members of the IL-1 family Dermal continue to be identified, adding to the complexity of DANGER SIGNALS dendritic cell Cell-wall components and other regulation of cutaneous inflammation29. products of pathogens that alert Both the epithelial barrier cells and resident innate the innate immune system to Dermis immune cells in the skin express pattern-recognition the presence of potentially harmful invaders, usually by receptors that recognize specific pathogen components interacting with Toll-like and can trigger downstream activation cascades. An CCL17 receptors and other pattern- E-selectin important subset of these receptors belong to the Toll- recognition receptors that are ICAM1 like receptor (TLR) family30–33,which bind pathogen- expressed by tissue cells and dendritic cells, for example. associated molecular pattern molecules such as Monocyte/ lipopolysaccharide34,bacterial lipoproteins35,36,flagellin37, macrophage/ 38 LANGERHANS CELLS NK cell yeast mannans and unmethylated CpG DNA Immature bone-marrow- Naive 39,40 T cell motifs . TLR expression is variable and might identify derived dendritic cells that Granulocyte subsets of innate immune cells, such as DCs, with spe- reside for long periods of time Dermal post-capillary venule 41–43 in the epidermis. They contain cific functions .DC activation through TLRs results Langerin and Birbeck granules, in increased production of pro-inflammatory cytokines express E-cadherin and bind Figure 1 | Immune-response elements in non-inflamed and antimicrobial peptides, increased nitric oxide syn- to contiguous keratinocytes. skin. Human skin is composed of three distinct thesis and enhanced bacterial killing, as well as increased Stimulation through Toll-like compartments relevant to its immune functions. First, the 30 receptors or other danger-signal epidermis is composed of keratinized epithelial cells and antigen presentation .The binding of TLR ligands is receptors causes them to migrate functions as both a physical barrier and an early warning associated with the recruitment of intracellular adaptor to the draining lymph node and system. Immune cells resident in the epidermis include proteins similar to those used by IL-1R and subse- mature into highly efficient specialized dendritic cells (DCs) known as Langerhans quent activation of the JUN N-terminal kinase (JNK) antigen-presenting cells. cells and intraepithelial lymphocytes. Second, the dermis is and nuclear factor-κB (NF-κB) signalling pathways30. mainly composed of connective tissue produced by dermal The NF-κB signalling pathway is seen as a key link ANTIMICROBIAL PEPTIDES fibroblasts. Immune system cells resident in non-inflamed Evolutionarily conserved dermis include dermal DCs, mast cells and a small number between the innate and adaptive immune systems. In peptides that directly bind to κ of cutaneous lymphocyte antigen (CLA)-positive memory the skin, NF- B regulates the expression of numerous and interact with cell surfaces T cells. Third, dermal post-capillary venules constitutively genes that are involved in the initiation of the inflam- of bacteria and fungi, usually express low levels of E-selectin, CC-chemokine ligand 17 inducing the formation of matory response, including adhesion molecules, pores, leading to the death (CCL17) and intercellular adhesion molecule 1 (ICAM1). chemokines and cytokines (such as IL-1 and TNF), of target cells. These support the margination and baseline emigration of matrix metalloproteases, nitric oxide synthase and CLA+ memory T cells into non-inflamed skin. CLA– T cells, enzymes that control PROSTANOID synthesis44.Beyond the including both naive cells and memory/effector cells that PROSTANOID direct effects of these compounds on pathogens and A member of the broad family are targeted to other tissues, as well as granulocytes
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