The activation of T lymphocytes is dependent upon the function of a number of cell surface proteins on T cells. A monoclonal antibody has been prepared to a non-polymorphic epitope on Ly-6 molecules, and this antibody is mitogenic for T lymphocytes. This observation strongly implicates Ly-6 molecules in participating in the initial signalling that results in activation of T lymphocytes. The experiments in this proposal will use this mitogenic anti-Ly-6 monoclonal antibody to define the mechanism by which Ly-6 molecules function to regulate T cell responses in vitro and to determine whether Ly-6 molecules function as an alternative pathway of murine T cell activation. The role of non-T accessory cells for polyclonal Ly-6 mediated T cell activation will be defined in part by comparing the capacity of different viable and paraformaldehyde fixed normal and tumor cell populations, and their isolated membranes, to provide the requisite accessory cell signals. We will also evaluate by limiting dilution analysis whether the capacity of anti-Ly-6 antibody to markedly augment specific T cell responses is due to the stimulation of increased numbers of antigen-specific T cells or is due to enhancement of antigen non-specific factors that are required for T cell clonal expansion. By cellular and genetic studies, we will determine the basis that accounts for the failure of T lymphocytes from A/J mice to be polyclonally activated via Ly-6 molecules. The capacity of lymphokines to regulate Ly-6 molecules will be characterized in vitro and the potential effect on lymphocyte function will be assessed, especially to obtain evidence of whether Ly-6 molecules may also be functional in B lymphocytes. Other investigations will be concerned with whether expression of Ly-6 molecules on T cells correlates with a unique stage of T cell differentiation, i.e. IL-2 secretion by helper cells. The studies are relevant to understanding the physiological function of Ly-6 molecules and to provide a new model with which to study the complex cellular and molecular interactions that are necessary to cause T cell activation. In view of the capacity of activation of T cells by Ly-6 molecules to increase antigen-specific responses, these studies are also relevant to development of strategies that may lead to enhanced immune function in patients with immunodeficiency diseases, e.g. AIDS.
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