T cell development in the thymus occurs as a sequential process from double negative (CD4-CD8- TcR-) to double positive (CD4+ CD8+ TcR+) to single positive (CD4+ CD8-, CD4- CD8+) cells. During the double positive to single positive transition antigen receptors on thymocytes initiate signals that select for cells with appropriate self/non-self recognition. Thymocytes that express receptors with no affinity for MHC/antigen die by neglect, cells with high affinity for self antigens die by apoptosis and cells with low affinity for self antigens undergo further differentiation. TCR signals alone do not effectively regulate positive and negative selection. Thymic development is also regulated by receptors capable of providing """"""""second signals"""""""" to TcR- activated cells. This project will characterize the activation responses initiated in DP thymocytes as a result of engaging TCR and CD28 and/or CD2 co-inducer receptors. These two sets of stimuli are being used as model agonists to comparatively characterize signaling pathways that regulate maturation or apoptosis. The nature and strength of the response initiated by these co-inducer receptors determines whether TCR-activated DP thymocytes mature to CD4+ CD8- cells or undergo apoptosis. Maturation and apoptotic responses stimulated by signals from TCR + CD28 are independent and separable components in the thymocyte maturation program. In addition, TCR engagement in DP thymocytes induces the expression of novel co-inducer receptors that stimulate arrest of thymocyte maturation. These analyses will determine how signals integrated from different co-inducer receptors stimulate cross-talk between signaling pathways that affects the outcome of thymocyte selection.
