The most critical event in the induction of most-immune responses is the activation of a resting CD4+ T cell by antigen. This step in the immune response appears to require not only the presentation of sufficient ligand for the T cell receptor but accessory signals as well. This step leads to the generation of both memory and effector T cells. This step in immune responses is very difficult to analyze in detail, as it has not been mimicked effectively in vitro, and is usually studied by in vivo priming with antigen. The goal of the present studies is to use anti-T cell receptor antibody as a substitute for antigen, and to characterize priming of T cells using a variety of detection systems, some of which may not require T cell proliferation. Four different types of information are being sought: First, can we define cell surface molecules, physical changes or intracellular events that define different stages of differentiation in CD4+ T cells, allowing us to place a given cell in a given activation state, and also allowing the measurement of transitions from one stats to another? Second, what are the requirements, both in terms of ligand and in terms of accessory cells or molecules derived from accessory cells, needed to drive a resting CD4+ T cell to memory or effector cells? Third, how do requirements for priming of D4+ T cells to become helper or inflammatory T cells differ? Finally, how do the activation requirements of T cells in different states of differentiation differ from one another, and what is the mechanism of this change? To carry out these studies, we will use monoclonal antibodies to the T cell receptor bound to cells or to plastic, or in soluble form, to stimulate resting or activated CD4+ T cells or cloned T cell lines representing different states of activation and different functional phenotypes, and compare activation requirements. Such assays will be used to identify and purify accessory cell molecules that contribute to in vitro priming. Monoclonal antibodies will be raised against these accessory cell factors and against cell surface molecules on cells in different states of activation so that we can accurately define activation state.
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