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 immune responses. The mechanisms of LC trafficking thus seem to be of particular relevance for the induction and maintenance of cutaneous immunity. LCs or their putative precursors express surface molecules that allow them to home to skin and localize in the epidermis for prolonged periods of time. Tissue injury, microbial infection, and other perturbants of epidermal homeostasis (eg, contact allergens) provide danger signals, leading to a local production of proinflammatory cytokines that induce LC mobilization to the lymphoid tissue. At the same time, signals are generated that recruit LC precursors into the skin to maintain the epidermal LC population. Distinct pairs of chemokines and their receptors control the migration from blood to epidermis and from there to the regional lymphatics. In addition, trafficking is controlled at the level of cell adhesion, where LCs downregulate some adhesion molecules to exit the epidermis and upregulate others to migrate across the extracellular matrix and home to T-cell areas of regional lymphoid tissue. The improved understanding of mechanisms that regulate LC trafficking might offer new opportunities for therapeutic interventions to suppress, stimulate, or deviate cutaneous immune responses.