Langerhans cells are epidermal antigen-presenting cells that function by taking up antigens in the skin, migrating to the lymph nodes, where they are designated interdigitating cells, and triggering the immune response. The role of interdigitating cells (IDC) was investigated in a murine model of herpes simplex virus-1 infection in the skin. The number of IDC in the lymph nodes began to increase on the first day following infection and reached a peak three days p.i. Low titers of infectious virus were recovered from the fraction of lymph node cells that consisted of 60-80% IDC at one day p.i. Lymph node cells that were obtained from mice immunized with HSV-1 proliferated in vitro in response to viral antigens but did not respond to mock antigens. When mice were immunized with HSV-1 inoculated into skin that had been depleted of Langerhans cells, this in vitro proliferative response was abolished. Thus, the present results suggest that Langerhans cells function in the immune defense of the skin against HSV-1 infection by transporting the virus to the peripheral lymph nodes where an immune response is initiated. Injection of the immunomodulator OK-432 into the footpad skin caused a local increase in the number of Langerhans cells in the epidermis and led to an increased migration of dendritic cells to the lymph nodes. Under these conditions, a decrease in HSV-1 pathogenicity was noted. These observations indicate that the pathogenicity of herpes simplex virus type 1 in the skin is affected by Langerhans cell density and activity in the epidermis and the lymph nodes.