Multistep navigation of Langerhans/dendritic cells in and out of the skin

Langerhans cells (LCs) are specialized antigen-presenting cells that reside in the epidermis as sentinels of the immune system. LCs constantly monitor the epidermal microenvironment by taking up antigen and processing it into fragments that can be recognized by cells of the adaptive immune response. Because of their unique migratory ability, LCs can transport antigen from the epidermis to regional lymph nodes, where they can initiate systemic imm une responses. The mechanisms of LC trafficking thus seem to be of particul ar relevance for the induction and maintenance of cutaneous immunity. LCs o r their putative precursors express surface molecules that allow them to ho me to skin and localize in the epidermis for prolonged periods of time. Tis sue injury, microbial infection, and other perturbants of epidermal homeost asis (eg, contact allergens) provide danger signals, leading to a local pro duction of proinflammatory cytokines that induce LC mobilization to the lym phoid tissue. At the same time, signals are generated that recruit LC precu rsors into the skin to maintain the epidermal LC population. Distinct pairs of chemokines and their receptors control the migration from blood to epid ermis and from there to the regional lymphatics. In addition, trafficking i s controlled at the level of cell adhesion, where LCs downregulate some adh esion molecules to exit the epidermis and upregulate others to migrate acro ss the extracellular matrix and home to T-cell areas of regional lymphoid t issue. The improved understanding of mechanisms that regulate LC traffickin g might offer new opportunities for therapeutic interventions to suppress, stimulate, or deviate cutaneous immune responses.