Circuits and signals of the skin-associated lymphoid tissues (SALT)

The existence of a specialized set of skin-associated lymphoid tissues (SALT) was proposed several years ago as a means of accounting for epidermotropism of certain malignant lymphocytes, immunocompetent cells within skin, and expression of histocompatibility antigens on cutaneous cells derived from hematopoietic precursors. The proposal was supported by observations of in vivo and in vitro antigen-presenting potential of epidermal Langerhans cells, discovery of novel bone marrow-derived cells within epidermis, and epidermotropism as a physiologic property of some nonmalignant T lymphocytes. Langerhans cells stand alone among epidermal cells in their capacity to process and present antigens of the intraepidermal compartment in highly immunogenic fashion. However, not all antigens within epidermis lead to hypersensitivity: antigens introduced into Langerhans cell-deficient skin are perceived as tolerogens, and the cellular source of the tolerogenic signal may be Thy-1-positive epidermal cells. An extracutaneous pathway for presentation of epidermally-administered antigen has been described, and is independent of Langerhans cells, genetically determined, and dominant in the face of epidermally derived tolerogenic signals. Only systemic unresponsiveness can mitigate the cutaneous sensitivity produced by the second pathway. Thus, both intra- and extracutaneous forces contribute to the induction and regulation of cutaneous immunity, forces that are integrated via SALT to achieve optimal cutaneous immune protection against pathogens and neoplasms.