This laboratory studies the role of the epidermis as an immunological organ. We study very early events which occur during allergic contact dermatitis which is a paradigm for studying the skin immune system. Within 24 hours after exposure of epidermis to haptens, there is """"""""activation"""""""" of Langerhans cells, as demonstrated by their expressing greatly increased amounts of class II MHC on their surfaces, and their becoming very potent antigen-presenting cells. There is an almost immediate upregulation of IL-1beta mRNA from Langerhans cells after hapten appli- cation, and later, an upregulation of IL-10 mRNA by keratinocytes. These cytokines exert functional effects on the skin, both in vivo and in vitro. Another area of intense interest is the nature of the precise epitopes generated after hapten-Langerhans cell interaction. Using Langerhans cells as antigen-presenting cells, we found that hapten-modified MHC class II binding peptides generate epitopes recognized by hapten- specific CD4+ T cells and that precise positioning of hapten molecules on peptides fitting into the groove of the MHC class II molecules is required for optimal CD4+ T-cell recognition in vitro and in vivo. The findings provide insight into how haptens are recognized by T cells in contact sensitivity. Another major area of study is that of the role of epidermal Langerhans cells in HIV disease. We have just completed a series of studies of the function of Langerhans cells in patients infected with HIV and the infectability of cultured dendritic cells by HIV. Allostimulation by Langerhans cells from HIV+ patients was impaired; however, results of identical twin pairs discordant for HIV serology indicate that protein antigen presentation by these cells was intact. Dendritic cells were productively infected at low levels with the monocytotropic and T cell tropic HIV. When dendritic cells were cocultured with normal T cells and HIV they exhibited normal antigen presenting functions yet transmitted virus to the T cells. Thus, immunologic dysregulation in early and intermediate stages of HIV disease does not reflect marked functional impairment of antigen presenting cells, but may be secondary to T cell dysfunction alone.
