Skin immune sentinels in health and disease

Abstract

Human skin and its immune cells provide essential protection of the human body from injury and infection. Recent studies reinforce the importance of keratinocytes as sensors of danger through alert systems such as the inflammasome. In addition, newly identified CD103(+) dendritic cells are strategically positioned for cross-presentation of skin-tropic pathogens and accumulating data highlight a key role of tissue-resident rather than circulating T cells in skin homeostasis and pathology. This Review focuses on recent progress in dissecting the functional role of skin immune cells in skin disease.

Figure 1. Skin anatomy and cellular effectors

The structure of the skin reflects the complexity of its functions as a protective barrier, in maintaining the body temperature, in gathering sensory information from the environment and in having an active role in the immune system. The epidermis contains the stratum basale, the stratum spinosum, the stratum granulosum and the outermost layer, the stratum corneum, which is responsible for the vital barrier function of the skin. Specialized cells in the epidermis include melanocytes, which produce pigment (melanin), and Langerhans cells. Rare T cells, mainly CD8⁺ cytotoxic T cells, can be found in the stratum basale and stratum spinosum. The dermis is composed of collagen, elastic tissue and reticular fibres. It contains many specialized cells, such as dendritic cell (DC) subsets, including dermal DCs and plasmacytoid DCs (pDCs), and T cell subsets, including CD4⁺ T helper 1 (T_H1), T_H2 and T_H17 cells, γδ T cells and natural killer T (NKT) cells. In addition, macrophages, mast cells and fibroblasts are present. Blood and lymphatic vessels and nerves (not shown) are also present throughout the dermis.

Figure 2. Keratinocytes as sensors of danger

Keratinocytes are central skin sentinels and can recognize foreign and dangerous agents, for example pathogen-associated molecular patterns (PAMPs) of microbial origin and danger-associated molecular pattern (DAMPs), such as irritants and toxins, through Toll-like receptors (TLRs) and the inflammasome machinery. TLRs are transmembrane receptors that are present on the cell surface or on the surface of endosomal compartments. Lipopolysaccharide (LPS) stimulates TLR4; bacterial lipoproteins and fungal zymosan stimulate TLR1–TLR2 and TLR2–TLR6 heterodimers; bacterial flagellin activates TLR5; unmethylated CpG motifs present in DNA function as stimulators of endosomal TLR9; double-stranded RNA (dsRNA) activates endosomal TLR3; and single-stranded RNA (ssRNA) activates TLR7, the expression of which is induced by TLR3 triggering (not shown). PAMP recognition by TLRs leads to activation of host cell signalling pathways and subsequent innate and adaptive immune responses with antimicrobial peptide, cytokine and chemokine production. Keratinocytes also express NLR family, pyrin domain containing 3 (NLRP3), which belongs to the newly identified class of proteins encoded by the nucleotide-binding domain, leucine-rich repeat-containing (NLR) gene family. These proteins can recognize PAMPs that are in the cytoplasm (such as LPS and flagellin), DAMPs and ultraviolet (UV) light, and activate the inflammasome complex. This multimeric complex is formed by an NLR, an adaptor protein termed ASC (apoptosis-associated speck-like protein containing a caspase recruitment domain) and pro-caspase 1, and its assembly leads to the activation of caspase 1, which processes pro-interleukin-1β (pro-IL-1β) into biologically active IL-1β.

Figure 3. Skin-resident immune sentinels

Ultraviolet (UV) light, trauma, irritants or infection (essentially any type of barrier disruption) triggers a coordinated immune response to maintain skin homeostasis. Skin-resident immune cells are key sentinels for restoring homeostasis but can also be effector cells during tissue pathology. Epidermal Langerhans cells are key immunological sentinels. Keratinocytes sense and react to noxious stimuli by producing pro-inflammatory cytokines (such as interleukin-1β (IL-1β), IL-6, IL-18 and tumour necrosis factor (TNF)), which in turn activate dermal dendritic cells (DCs) in the presence or absence of antigen encounter. Innate immune cells, such as plasmacytoid DCs (pDCs), activated by stress signals derived from keratinocytes, can also contribute to dermal DC activation by releasing interferon-α (IFNα). Fibroblasts can produce TNF and IL-6 and natural killer T (NKT) cells can produce TNF and IFNγ, thereby contributing to the local inflammatory response. Dermal DCs activate and promote the clonal expansion of skin-resident memory CD4⁺ or CD8⁺ T cells. T cell-derived pro-inflammatory cytokines and chemokines in turn can further stimulate epithelial and mesenchymal cells, including keratinocytes and fibroblasts, thus amplifying the inflammatory reaction. Moreover, skin-resident T cells can migrate into the epidermis, engaging in an immune–epithelial cell crosstalk.

Figure 4. Unconventional T cells in the skin

Unconventional T cells, such as γδ T cells and natural killer T (NKT) cells, are involved in skin immunosurveillance. Both γδ T cells and NKT cells are cytolytic and release granzyme B and perforin and cause apoptosis of transformed or infected cells. They activate dermal dendritic cells (DCs) by producing tumour necrosis factor (TNF) and interferon-γ (IFNγ). Moreover, γδ T cells produce growth factors that are essential for wound healing, such as connective tissue growth factor (CTGF), fibroblast growth factor 9 (FGF9; also known as GAF) and keratinocyte growth factor (KGF). Finally, both γδ T cells and NKT cells produce cytokines that are usually associated with T helper 1 (T_H1), T_H2 and T_H17 cells.

Figure 5. Psoriasis immunopathogenesis

Environmental factors trigger psoriasis in genetically predisposed individuals carrying susceptibility alleles of disease-associated genes. In the initiation phase, stressed keratinocytes release self DNA that forms complexes with the cathelicidin antimicrobial peptide LL37, which in turn activates plasmacytoid dendritic cells (pDCs) to produce interferon-α (IFNα). Keratinocyte-derived interleukin-1β (IL-1β), IL-6 and tumour necrosis factor (TNF) and pDC-derived IFNα activate dermal DCs. Activated dermal DCs then migrate to the skin-draining lymph nodes to present an as yet unknown antigen (either of self or of microbial origin) to naive T cells and promote their differentiation into T helper 1 (T_H1) and/or T_H17 cells. T_H1 cells (expressing cutaneous leukocyte antigen (CLA; not shown), CXC-chemokine receptor 3 (CXCR3) and CC-chemokine receptor 4 (CCR4)) and T_H17 cells (expressing CLA and chemokine receptors CCR4 and CCR6) migrate via lymphatic and blood vessels into psoriatic dermis, attracted by the keratinocyte-derived chemokines CCL20, CXCL9, CXCL10 and CXCL11, which ultimately leads to the formation of a psoriatic plaque. T_H17 cells secrete IL-17A, IL-17F and IL-22, which stimulate keratinocyte proliferation and the release of β-defensin 1, β-defensin 2, S100A7 and S100A9 and the neutrophil-recruiting chemokines CXCL1, CXCL3, CXCL5 and CXCL8. Moreover, inflammatory DCs produce IL-23, nitric oxide (NO) radicals and TNF. At the dermo–epidermal junction, memory CD8⁺ cells expressing very-late antigen-1 (VLA1) bind to collagen IV, allowing entry into the epidermis and contributing to disease pathogenesis. Cross-talk between keratinocytes, producing TNF, IL-1β and transforming growth factor-β (TGFβ), and fibroblasts, which in turn release keratinocyte growth factor (KGF), epidermal growth factor (EGF) and TGFβ, contribute to tissue reorganization and deposition of extracellular matrix (for example, collagen and proteoglycans). Figure is modified, with permission, from REF. © (2009) Massachusetts Medical Society.