The generation and differentiation of memory CD8 T cell responses in health and disease

Memory CD8 T cells provide protection to immune hosts by eliminating pathogeninfected cells during re-infection. While parameters influencing the generation of primary (1) CD8 T cells are well established, the factors controlling the development of secondary (2) CD8 T cell responses remain largely unknown. Here, we address the mechanisms involved in the generation and development of 2 memory (M) CD8 T cells. We observed that the time at which 1 M CD8 T cells enter into immune response impacts their fate and differentiation into 2 M CD8 T cells. Late-entry of 1 M CD8 T cells into an immune response (relative to the onset of infection) not only facilitated the expression of transcription factors associated with memory formation in 2 effector CD8 T cells, but also influenced the ability of 2 M CD8 T cells to localize within the lymph nodes, produce IL-2, and undergo Ag-driven proliferation. The timing of stimulation of 1 M CD8 T cells also impacted the duration of expression of the high-affinity IL-2 receptor (CD25) on 2 effector CD8 T cells and their sensitivity to IL-2 signaling. Importantly, by blocking or enhancing IL-2 signaling in developing 2 CD8 T cells, we provide direct evidence for the role of IL-2 in controlling the differentiation of 2 CD8 T cell responses. Thus, our data suggest that the process of 1 M to 2 M CD8 T cell differentiation is not fixed and can be manipulated, a notion with relevance for the design of future prime-boost vaccination approaches.