Due to the growing burden of malignancy and chronic infections, manipulating CD8+ T cell responses for clinical use has become an important goal for immunologists. CD8+ T cells have the unique capacity to recognize and kill tumor cells and intracellular pathogens. Thus far, failed or only minimally effective T cell vaccines against chronic pathogen infections and tumors have highlighted basic knowledge gaps for eliciting memory CD8+ T cell protection. Defining the immunological mechanisms that determine protective capacity and longevity in T cells will be critical to both therapeutic and prohylactic vaccine efficacy.
My studies focus on strategies to manipulate effector and memory CD8+ T cell responses, including their mechanisms of action. Specifically, I show that dendritic cell (DC) immunization coupled with relatively early (days 1-3) or late (days 4-6) administration of enhanced IL-2 signals drive either effector or memory programs. DC + IL-2c administered 4-6 days post-DC transfer is shown to enhance Ag-specific effector CD8+ T cell responses; this approach is further explored in the context of a cancer immunotherapy, demonstrating effective control of tumor burden in multiple murine models of cancer. Temporal alterations of IL-2 signaling from day 4-6 to day 1-3 post-DC immunization is shown to increase memory potential and memory CD8+ T cell numbers long-term. Additional studies reveal CTLA-4-mediated down-regulation of B7-ligands on DCs after IL-2c treatment, demonstrating that weaker or more transient signaling through the CD28-B7 axis may favor memory CD8+ T cell programs. My work contributes valuable concepts in memory CD8 T cell generation to develop T cell vaccines that are both safe and predictable.