DISTINCT T CELL ACTIVATION BY ANTIGEN PRESENTING CELLS

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Application of otherwise sensitizing haptens to ultraviolet irradiated skin induces T cell-mediated immunologic tolerance. Along with other changes in the cutaneous milieu, alterations in antigen presenting cell (APC) populations in the epidermis occur after UV exposure. Six to 72 hours after UV exposure, infiltrating macrophages (UV-Mph) replace the normal, indigenous dendritic APC, Langerhans cells, as the predominant APC of epidermis. These UV-Mph have been shown to induce antigen specific tolerance in mice and are associated with tolerance in humans. The basic hypothesis driving my work is that these two APC, LC and UV- Mph, which are associated with the distinct immune outcomes of sensitization and tolerization, respectively, activate T cells in distinct ways. The proposed research will determine whether differences in costimulatory molecules exist between LC and UV-Mph, and if so, whether these are involved in distinct activational states of the T cells with which they interact. Thus, flow cytometric analysis of the relative expression of B7-1, B7-2, CD40, VCAM-1 and fibronectin by UV-Mph and LC will be performed. The functional significance of differences will be explored by determining the effect on T cell activation of manipulations that alter the expression of these molecules or their ability to send or receive signals. The T cell effects to be measured are lL-2Ra (CD25) expression by flow cytometry, growth by tritiated thymidine incorporation, and cytokine production (IL-2, IL-4, IL-5, IFN-g) by ELISPOT. Manipulations of the system are to be addition of recombinant cytokines to alter costimulatory molecule expression, blocking antibodies to costimulatory molecules or their T cell ligands, and addition of neutralizing antibodies to candidate growth factors (lL-2, lL-4, lL-7 and IL-15). The expected results are that previously published differences in T cell CD25 expression are due to different utilization of costimulatory molecules. These differences also lead to different T cell growth factor use and cytokine production after activation by these two APC.