Langerhans cells (LC) are skin-specific members of the dendritic cell (DC) family of antigen presenting cells. As members of this family, LC activate immunologically naive, antigen-specific T cells with high efficiency and, as residents of epidermis, are outermost sentinels for the immunologic recognition of environmental antigens, infectious microorganisms, and malignancies. Solar ultraviolet radiation between 295 and 320 nm (UVB) is responsible for sunburn and for the majority of skin cancers in humans. UVB radiation also prevents the immunological recognition of novel antigens, including contact sensitizers and tumor antigens in skin. Our working hypothesis is that UVB radiation exerts this effect (i.e., induction of immunological tolerance) by preventing the maturation of Lc into fully competent DC. Taking advantage of novel lines of Ia+ antigen presenting cells (XS lines) derived from newborn mouse epidermis, we propose four Specific Aims: 1) To confirm that XS lines are representative of epidermal l-C through precursor frequency analysis and cloning, phenotypic and functional comparisons with newly established short-term LC lines, and comparisons with other DC lines. 2) To study mechanisms of maturation in XS lines under the influence of different growth media, cytokines, reactive haptens, and a phorbol ester. Functional properties assessed at different states of maturation will include expression of surface molecules, production of cytokines, immunization with reactive haptens, and education of Th0 cells into Th1 or Th2 subsets. 3) To characterize mechanisms by which UVB radiation modulates the function of LC. We will study the impact of UVB on XS cell maturation and determine whether incomplete maturation accounts for distorted APC function (i.e., induction of clonal anergy in Th1 cells and/or preferential activation of Th2 cells). 4) To study the UVB- signalling pathways that lead to impaired antigen presenting function, by identifying UVB-inducible immediate early genes (IEG) in XS cells, characterizing chromophores and mediators responsible for IEG activation and functional changes. These studies of molecular mechanisms of UVB- induced damage to antigen-presenting cells in skin will provide new knowledge that ultimately may lead to the development of pharmacological agents to prevent the detrimental effects of solar radiation.
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