The objectives of this proposal are to extend our studies of human immune responses in vitro to simple chemical determinants. Proliferative and cytotoxic T cell responses to cells modified with the haptens trinitrophenyl (TNP), dinitrohpenyl (DNP), and fluorescein isothiocyanate (FITC) will be investigated. Cellular and molecular requirements for stimulation of seconday in vitro responses will be compared with those for induction of primary responsiveness. The roles of particular subpopulations of monocytes/macrophages will be defined, including macrophage lines with distinct functional activities and cell surface phenotype. Requirements for antigen presentation by hapten-modified cells will be compared with those for induction of responses to the same haptenic determinants presented on membrane fragments or soluble protein carriers. Regulation of T cell responses to haptens by T cell and macrophage subpopulations will be investigated and attempts will be made to identify and characterize soluble regulatory factors. Hapten-specific T cell lines and T cell clones will be established in an effort to more precisely define specificities for haptenic and MHC determinants, and to prepare clonally-derived and phenotypically-characterized populations with specific functional activities. Finally, we will explore a new model recently developed in our laboratory for inducing exaggerated responsiveness to autologous and allogeneic Ia determinants through BUdR and light suicide of pokeweed mitogen-stimulated cells. The proposed experiments will enhance our understanding of several important issues in immunobiology, including requirements for antigen presentation, definition of functional subpopulations of human lymphoid cells, and elucidation of the role of MHC molecules in both primary and secondary human immune responses to conventional antigens. They will have particular relevance to our efforts to understand the induction and regulation of responses to antigens that may be physiologically presented as intrinsic cell surface molecules (e.g., tumor or vial antigens). They may also lead to novel insights into fundamental mechanisms involved in the pathogenesis of autoimmune processes.
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