FUNCTIONAL ANALYSIS OF HUMAN HELPER T CELL CLONES

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Over the past three years, the attention of our laboratory has been focused on the isolation and long term in vitro growth of cloned antigen specific human T cells propagated as interleukin-2 (IL-2) dependent T cell lines (TCL). We have been particularly interested in analyzing T cells specific for hapten (trinitrophenyl (TNP)) modified autologous cells, as a model of human T cell immunity to virus and tumor antigens. During the course of these studies, we have successfully established in long term culture cloned helper TCL specific for a wide variety of antigens, including: hapten, soluble antigens, and alloantigens. Moreover, the functional analysis of these cloned TCL has identified several novel immunoregulatory pathways which govern both humoral and cell mediated immune reactions. The major thrust of the present proposal will be to continue to define the specificity, genetic restrictions, and mechanisms of action of regulatory human T cell clones. Specifically, our goals are to: 1) improve culture methodologies for the long term IL-2 dependent growth of cloned human T cells, with particular emphasis on optimizing conditions for the consistent growth of suppressor cells; 2) analyze the soluble factor(s) and direct cell-cell interactions by which antigen specific helper T cell clones collaborate with various B cell subsets, macrophages, and other T cells; this will include the study of antigen specific helper T cells specifically targeted to amplify either humoral or cytolytic T cell (CTL) responses; and 3) utilize cloned autologous antigen specific TCL as immunogens for the in vitro generation of anti-auto idiotypic T cell clones which down regulate immune responses in an antigen specific manner. The assay systems utilized, the cloned TCL generated, and the information gained in the study of normal regulatory interactions should extend naturally to a more precise analysis of human disease states characterized by disordered immunoregulation; specifically autoimmune states and the spectrum of immunodeficiency syndromes, including AIDS.