T CELL ACTIVIATION BY DISTINCT ANTIGEN PRESENTING CELLS

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Exposure of humans and experimental animals to ultraviolet irradiation (UV) can lead to immunologic tolerance. Langerhans cells (LC) are the predominant antigen presenting cell (APC) of normal unirradiated epidermis. After exposure to UV, LC are replaced by infiltrating macrophages (UV-Mph) as the dominant APC of epidermis. Because different immune outcomes are initiated by these two APC, we hypothesized that their interactions with T cells would be different. Using alloantigen presentation with fresh human cells, we show several differences exist. 1) Distinct costimulatory molecule expression: Relative to LC, UV-Mph express less B7-1, B7-2 and CD40, more LFA-1, and comparable ICAM-1, ICAM-3 and LFA-3. 2) Distinct costimulatory molecule utilization: UV-Mph-, but not LC-stimulated T cell growth is CD49e (alpha5 integrin)-dependent. 3) Distinct T cell growth factor use: In contrast to LC-, UV-Mph-stimulated T cell growth is independent of IL-2, IL-7, and IL-15 and dependent on IL-4. 4) Distinct activation gene expression: In contrast to LC-, UV-Mph-stimulated T cells are deficient in their ability to express IL-2Ralpha, which is critical to formation of the high affinity IL-2 receptor. 5) Distinct cytokine production: In contrast to LC-, UV-Mph-stimulated T cells produce IL-4 and IL-5, cytokines associated with immunologic tolerance. The comparison of T cell activation by these two APC provides a model system in which distinct signals are provided to T cells, which respond in distinct manners. In the present application, I propose to investigate, under the guidance of recognized experts in the field, the signal transduction events that mediate the different outcomes of T cell activation by these two, in vivo-derived human APC. Specifically, using electromobility shift assays, supershift assays, kinase assays, immunoprecipitation and western blot analysis I will elucidate the pathways that allow UV-Mph to activate T cell growth and IL-2 expression despite deficient IL- 2Ralpha expression. Postulated mechanisms include reduced NF-kappaB2 expression (because of reduced CD28 signals), and enhanced AP-1 or NF-AT expression (because of increased VLA-5 signals). Signaling through VLA-5 is hypothesized to be transduced via the receptor tyrosine kinase, MAP kinase pathway.