Cross-linking and conformational change in T-cell receptors: role in activation and in repertoire selection

TCRs undergo a series of interactions with ligands during development. We have characterized the interaction of a TCR with its ligand and the attendant co-receptor and co-ligand structures. This characterization has led to the model in which the TCR not only binds to class II MHC, but also binds to CD4 co-receptors and co-ligands such as Mls. We have shown that both cross-linking and conformational change in the TCR are required for optimal T-cell activation. Finally, we have used the observation that a particular self-peptide found abundantly associated with class II MHC in the periphery is essentially lacking from thymic cortical epithelium to argue that positive selection for self-MHC recognition may occur by a novel process in the thymic cortex. A TCR recognizing class II MHC with low affinity could either be multiply cross-linked in the absence of conformational change, which here would be driven by a unique peptide, or could be conformationally changed without cross-linking due to the rarity of the individual high-affinity peptide on thymic cortical epithelial cells. Either proposal leads to a partial signal one delivered via the TCR, which we refer to as signal one-half. This signal one-half would induce the cell to repress its other co-receptor molecule and to undergo maturation events such as up-regulation in TCR expression. Such cells are then rigorously screened for activating interactions with autologous structures, such as Mls. The threshold for clonal deletion is set very low to avoid autoreactivity. By this combination of signaling events, a mature TCR repertoire is generated that has the functional characteristics observed in immune systems.