REGULATORY MECHANISMS IN THE IMMUNE SYSTEM

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DESCRIPTION (provided by the applicant): We propose to study two aspects of the question of how T cells with alpha, beta receptors recognize antigens bound to class II major histocompatibility (MHC) molecules. 1) While in most cases this recognition involves a peptide antigen, T cell hypersensitivity to metals such as nickel (Ni) is common in the human population, suggesting that metal cations can become a specific part of a T cell ligand. We propose to establish the structural basis for this recognition for Ni++. We will use an alpha, beta TCR specific for Ni++ presented by the DRbeta3*0301 MHC molecule isolated from a patient with Ni sensitivity. We will determine how the Ni++ ion becomes part of the MHC ligand and how that MHC/Ni++ complex interacts with the alpha, beta TCR. 2) When a T cell confronts an antigen, it may or may not become activated and start a productive immune response. One of the factors controlling this outcome is quality of the interaction between the alpha, beta TCR and the MHC associated antigen. There is still some question which is more important: The overall strength of this interaction or the length of time an individual molecule or receptor stays bound to an MHC/antigen molecule. To answer this question, we propose to use a number of biophysical and flow cytometry methods to construct a database of measurements for a large set of well characterized T cell clones correlating the kinetics of receptor engagement to the efficiency with which the T cell becomes productively activated. .