White blood cells called T lymphocytes play critical roles in immune defense against viruses, bacteria, fungi, protozoa, and cancer cells. They are also involved in allergies / and in autoimmune diseases. T cells develop in a gland called the thymus, where they learn to distinguish the natural components of the body from the mutant proteins in tumor cells or those produced by infectious agents. This involves allowing cells with useful surface receptors to mature and eliminating cells with inappropriate receptors before they can become dangerous. This selection must work properly to generate T cells needed for effective responses to invading organisms and cancer, without allowing development of those cells harmful to normal body tissues. One goal of our work is to understand how this ?education / selection? process occurs. Because T receptors see foreign substances (antigens) in the form of peptide-major histocompatibility complex (MHC) molecule complexes, we also wish to know how such materials guide development in the thymus and the activities of mature T cells in the body.During the past year we reported that during thymocyte maturation there are programmed changes in how the T cell receptor responds when bound to self-peptide:MHC molecule ligands. These maturational changes allow T- cells to make a useful functional distinction between foreign substances (antigens) to which immune responses are desirable and self proteins, to which immune responses are undesirable and potentially harmful. Our work has revealed a role for dendritic cells in positive selection and firmly established the requirement for persistent receptor signaling throughout the maturation process. We have isolated genes whose expression varies among the several well-defined stages of T-cell maturation and have validated a new method for rapid functional analysis of each of these. Finally, we have been able to separate thymocyte lineage commitment to the CD4 or CD8 pathways from subsequent differentiation in each of these pathways, to determine the role of ligand quality and coreceptor signaling in making the commitment decision, and to reveal the distinct role of Notch-1 signaling in mediating post-commitment maturation of cells in the CD8 lineage. - Thymus; positive selection; negative selection; TCR signaling; lineage choice; CD4; CD8.
