Generation of a normal peripheral T cell repertoire requires that T cell precursors proliferate, differentiate, and migrate through thymic stroma while surviving rigorous selective pressures. Recent work has shed light upon the complex molecular bases of pre-T cell migration and both positive and negative selection of immature T cells. Signaling through the T cell antigen receptor (TCR) and pre-TCR is required for selection and is dependent upon the function of numerous molecular intermediates, including members of a group of scaffolding or adapter proteins. Several adapters, including SLP-76 and LAT, play critical and non-redundant roles in thymocyte selection. One SLP-76-associated molecule, Adhesion and Degranulation-promoting Adapter Protein (ADAP), is an hematopoietic-specific adapter protein previously shown to play key roles in mature T cell adhesion, integrin activation, and activation. Preliminary data now reveal that ADAP is also required for generation of normal T cell numbers, and for effective positive and negative selection. The mechanism of ADAP action in promoting thymocyte maturation is unknown. Experiments described in this proposal will test hypotheses that ADAP regulates thymocyte adhesion, motility, and proliferation and that ADAP functions to couple the TCR-dependent signaling machinery with actin cytoskeletal rearrangement. These investigations will probe the role of ADAP in murine thymocyte signaling and development using cell biologic, biochemical, and genetic techniques. Information gained from these studies will improve understanding of the biochemical mechanisms underlying crucial T cell developmental processes, and will likely provide new insight into potential targets for therapy of autoimmune or immune deficiency disorders.
