Among cutaneous cells, epidermal Langerhans cells occupy a singular position with regard to antigen processing and presentation leading to the induction and expression of immunity to cutaneous pathogens. The long term goals of this project are to describe and analyze the precise cellular and molecular mechanisms by which Langerhans cells perform their physiologic functions, and to understand the consequences for cutaneous immunity and the pathogenesis of skin diseases that occur when these cells are injured. Langerhans cells carry out their physiologic activities in the cutaneous environment where their functions can be modified directly by their epidermal neighbors (keratinocytes, Thy 1+ dendritic epidermal cells) and indirectly by cells of the dermis and draining with lymph nodes through and to which activated Langerhans cells migrate after escaping the epidermis. Therefore, a thorough understanding of Langerhans cells requires that their functional properties be studied in the cellular and molecular context of the physiologic environment in which they normally reside.
The Specific Aims are based on the following hypothesis: Langerhans cells exist in two functionally different states in vivo: intraepidermal Langerhans cells efficiently process antigens and can present them to previously primed T cells, but are ineffective at presenting antigen to naive T cells; post- epidermal Langerhans cells (within the dermis or draining regional lymph nodes) are less able to process native antigen, but acquire the unique capacity to present antigens to unprimed T cells.
Specific Aims : 1. Analyze differences in vitro in antigen processing and presenting capabilities of fresh and cultured Langerhans cells. 2. Analyze contributions made in vivo by epidermal and dermal cells to induction of contact hypersensitivity through normal and experimentally perturbed skin. 3. Determine in vivo the immunizing of fresh and cultured Langerhans cells. Based on the hypothesis that fresh and cultured Langerhans cells correspond to intraepidermal and post-epidermal Langerhans cells in vivo, these strategies will be united in experiments that explore and exploit the genetic mechanisms responsible for the fact that some, but not all, individuals fail to develop contact hypersensitivity when exposed to ultraviolet light and hapten. Experimental use of hapten-induced contact hypersensitivity and its perturbation by ultraviolet light and by cytokines affords exploitable model systems for the study of the important link that exists between sun exposure, effects on the immune system, and development of skin cancer.
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