Professional antigen presenting cells

The Langerhans cells (epidermis) and dermal dendritic cells are the outermost sentinels of the cellular immune system (Fig. 1). They are dendritic, bone marrow-derived cells. Langerhans cells are characterized ultrastructurally by a unique cytoplasmic organelle known as the Birbeck granule. Recent work has shown the important role ultraviolet radiation plays in inducing photoimmunosuppression, which is mediated by effects on the skin dendritic cell population.

Fig. 1 Langerhans cell.

The dendritic Langerhans cells form a network in the epidermis. In this section, the Langerhans cells have been stained with a monoclonal antibody to HLA-DR.

T lymphocytes

T cells are defined by expression of the T cell receptor (TCR), the structure of which determines the foreign antigens the T cell will recognize. Consequently, TCR specificity is closely regulated to prevent circulation of T cells strongly recognizing self-proteins. The TCR recognizes the antigen as presented by the major histocompatibility complex (MHC) and this interaction is stabilized by CD8⁺ (MHC class I) or CD4⁺ (MHC class II) molecules.

T lymphocyte circulation through normal skin for immunosurveillance is regulated by lymphocyte surface molecules that promote ‘skin homing’, including cutaneous leucocyte antigen (CLA), CCR4, CCR6 and CCR10. Epithelial danger signals induced by infection and inflammation increase cutaneous and endothelial expression of skin homing receptor ligands thereby enhancing the influx of lymphocytes into the cutaneous compartment.

Different types of T cell with differing functions are recognized in the skin, for example:

Fig. 2 CD4⁺ T cell subsets.

The cytokine/function polarization of CD4⁺ T cells, which was until recently limited to the Th1/Th2 paradigm, has been expanded. Cytokines that are critical to lineage development are indicated in the arrow boxes. Below the cells are the effector or regulatory cytokine repertoires of each cell type (nTreg are contact dependent) and their abbreviated names.

Mast cells

Mast cells are principally known for their ability to degranulate and release histamine and other vasoactive molecules. This is very rapid because the granules are preformed. Degranulation arises in response to cross-linking of the high-affinity IgE receptor. Cross-linking arises when IgE molecules on the surface of the receptors bind the same protein antigen. Mast cells also synthesize a wide range of cytokines, and experimental models support the concept that mast cells play an important role in skin immune responses. Mast cells are normal residents of the dermis, and their circulating counterparts are basophils. Mast cell numbers increase during inflammatory reactions.

Keratinocytes

Keratinocytes synthesize antimicrobial peptides, produce proinflammatory cytokines (especially IL-1) and express immune reactive molecules such as major histocompatibility complex (MHC) class I and II molecules on their surface. They signal to cutaneous dendritic cells and have been shown to be able to induce specific dendritic cell: T cell functional outcomes. For example, keratinocyte production of thymic stromal lymphopoietin (TSLP) induces dendritic cells to drive T cells towards an inflammatory Th2 phenotype.

Eosinophils

Eosinophils are richly packed with potent mediators of inflammation and cytokines important in regulation of Th2-type immune responses.

Complement

Activation of the complement cascade down either the classical or the alternative pathways results in molecules that have powerful effects. These include opsonization, lysis, mast cell degranulation, smooth muscle contraction and chemotaxis for neutrophils and macrophages.