Immunological memory or the ability of the immune system to respond with enhanced vigor to pathogens/antigens encountered in the past is a central concept in immunology. This exaggerated recall immune response is the basis of vaccination against infectious diseases. The existence of immunological memory has been recognized for over 2000 years, yet our understanding of this phenomenon is limited, primarily because memory lymphocytes cannot be unequivocally identified as they lack specific, permanent markers. A novel genetically engineered mouse model system in which memory T cells and their immediate precursors are irreversibly will be used to answer fundamental questions in CD8 and CD4 T cell memory. CD8 T cell memory is a crucial arm of the immune system because CD8+ cytotoxic T cells are critical in controlling parasitic, intracellular bacterial and viral infections. CD4 T cells play a central role in modulating immune by providing help for the clonal expansion and affinity- maturation of antigen-specific B cells and cytotoxic CD8 T cells. In addition, CD4 T cells can act as cytotoxic effectors themselves. This five-year proposal is conceived as the beginning of a long-term program designed to understand the cellular and molecular basis of T cell memory. The objectives of this first grant proposal are three-fold: To establish where CD8 and CD4 memory T cells are generated (Specific Aim 1 and 2) To characterize the cell-cell interactions and clonal dynamics that occur during the course of a viral response (Specific Aims 1 and 2) To identify when the commitment of activated CD8 T cells to become memory CD8 T cells occurs (Specific Aim 3) Together these studies will lay the foundation for a better understanding of the mechanisms involved in memory CD8 and CD4 T cell development. The characterization of these processes will provide key information for designing efficient vaccines that provide long-term protective immunity.
