Cytotoxic T lymphocyte (CTL) interaction with an antigen-bearing cell results in generation of transmembrane signals that activate functional responses, including degranulation and delivery of the 'lethal hit' to kill the target cell. Recognition and signaling are determined by the antigen-specific T cell receptor (TCR), but additional """"""""accessory' proteins on the CTL also contribute as a result of interactions with their ligands on the target cell. These can be studied by using purified ligands presented to the T cell on artificial cell surface constructs; an approach which allows the relative contributions of the various receptors to adhesion and signal generation to be delineated. Using this approach, work done during the previous granting period has provided evidence that CTL activation involves a cascade of adhesion and signaling events initiated by the TCR and propagated by CD8 and other 'accessory' receptors including LFA-1 and fibronectin receptor (FN-R). Minimal TCR engagement does not activate the PI pathway or degranulation, but does provide a signal needed to convert CD8 from an inactive form to an active form able to mediate adhesion to class I MHC protein. Upon binding to class I, CD8 delivers a costimulatory signal which initiates PI hydrolysis and degranulation. Furthermore, preliminary evidence suggests that there is an 'off' signal to convert CD8 back to the inactive state to allow de-adhesion to occur. Planned work will focus on developing a better understanding of these signaling events and of the mechanism(s) by which CD8 becomes activated to bind class I and generate the costimulatory signal.
Specific Aims : (1) To identify the TCR-dependent signal(s) for 'activating' CD8 (the 'on' signal), (2) To characterize the CD-dependent costimulatory signal, (3) To identify and characterize the 'off' signal for de-activating CD8, and (4) To determine the mechanism by which CD8 becomes activated to mediate adhesion to class I protein. It is anticipated that the proposed studies will provide a better understanding of the complex set of ligand binding/signaling events that mediate CTL recognition and lysis of foreign cells; an understanding which should contribute to more effective manipulation of these responses for protective and therapeutic purposes in viral and neoplastic diseases.
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