Fig. 11.28 Expression of the IL-7 receptor (IL- 7Rα) indicates which CD8 effector T cells can generate robust memory responses. Mice expressing a T-cell receptor (TCR) transgene specific for a viral antigen from lymphocytic choriomeningitis virus (LCMV) were infected with the virus, and effector cells were collected on day 11. Effector CD8 T cells expressing high levels of IL-7Rα (IL-7Rαhi, blue) were separated and transferred into one group of naive mice, and effector CD8 T cells expressing low IL-7Rα (IL-7Rαlo, green) were transferred into another group. Three weeks after transfer, the mice were challenged with a bacterium engineered to express the original viral antigen, and the numbers of responding transferred T cells (detected by their expression of the transgenic TCR) were measured at various times after challenge. Only the transferred IL-7Rαhi effector cells could generate a robust expansion of CD8 T cells after the secondary challenge.
Among the important markers of memory T cells is the α subunit of the IL-7 receptor (IL-7Rαor CD127). Naive T cells express IL-7Rα, but it is rapidly lost upon activation and is not expressed by most effector T cells. For example, the experiment shown in Fig. 11.28 examines mice infected with lymphocytic choriomeningitis virus (LCMV). Around day 7 after infection, a small population of approximately 5% of CD8 effector T cells expressed high levels of IL-7Rα. Adoptive transfer of these IL-7Rαhi cells, but not IL-7Rαlo effector T cells, could provide functional CD8 T-cell memory to uninfected mice. This experiment suggests that memory T cells arise from effector T cells that maintain or reexpress IL-7Rα, perhaps because they compete more effectively for the survival signals delivered by IL-7.
The homeostatic mechanisms governing the survival of memory T cells also differ from those for naive T cells. Memory T cells divide more frequently than naive T cells, and their expansion is controlled by a shift in the balance between proliferation and cell death. As illustrated in Fig. 11.29, naive T cells require contact with self peptide:self MHC complexes in addition to cytokine stimulation for their long-term survival in the periphery (see Fig. 9.4). As with naive cells, the survival of memory T cells requires signaling by the receptors for the cytokines IL-7 and IL-15. IL-7 is required for the survival of both CD4 and CD8 memory T cells. In addition, IL-15 is critical for the long-term survival and proliferation of CD8 memory T cells under normal conditions. It also appears that memory T cells are less dependent on contact with self peptide:self MHC than naive T cells and are more sensitive to cytokines.
Memory T cells still require contact with peptide:MHC complexes to become reactivated during a secondary encounter with pathogen, but are also more sensitive to restimulation by antigen than are naive T cells. Furthermore, they more quickly and more vigorously produce several cytokines such as IFN-γ, TNF-α, and IL-2 in response to such stimulation. A similar progression occurs for T cells in humans after immunization with a vaccine against yellow fever virus.