T Cell Memory to Viruses

Chronic viral infections are characterized by a state of T cell dysfunction that is associated with expression of the PD-1 (programmed cell death 1) inhibitory receptor. A better understanding of the mechanisms that regulate CD8 T cell responses during chronic viral infection is required to improve immunotherapies that will increase T cell function and reduce viral load. We have recently identified a novel population of PD-1+ TCF-1+ virus specific CD8 T cells that act as stem cells to maintain T cell responses during chronic infection of mice with lymphocytic choriomeningitis virus (LCMV). The studies proposed in the application are focused on understanding how these virus specific stem-like CD8 T cells are generated and maintained during chronic infection and how this information can be used to develop rational approaches for optimizing PD-1 directed immunotherapy. In particular, we ask the following questions: 1) How do these cells maintain their quiescence and the stem-like state while living in a sea of antigen and getting TCR signals? 2) Are there any novel inhibitory pathways that are selectively expressed by the stem-like CD8 T cells to maintain their lifestyle during chronic infection? 3) How can we increase the number of these crucial stem-like CD8 T cells? 4) What are the most optimal PD-1 combination therapies for harnessing the full potential of the stem-like CD8 T cells? The following specific aims are proposed to address these questions: Specific Aim 1: Determine the role of inhibitory molecules selectively expressed by virus-specific stem-like CD8 T cells in regulating their quiescence and effector cell output. Specific Aim 2: Harnessing the potential of PD-1+ stem-like CD8 T cells for optimal immunotherapy in chronic viral infection.