| Memory CD8 T cells can provide long-lived immunity against pathogenic reinfection. As such, knowledge of the factors that contribute to the development, function and maintenance of memory CD8 T cells could be critical in the design of new vaccines. Signals derived from the cytokines IL-2, IL-7 and IL-15 have been shown to be critical for the development of an effective memory CD8 T cell response. In particular, the expression of the receptor for IL-7 (IL-7Ralpha) marks those cells with an increased proclivity to become memory cells from those more likely to initiate apoptosis. To determine whether IL-7Ralpha and IL-7 signals were sufficient for the production of memory CD8 cells we transgenically over-expressed IL-7Ralpha (IL-7Ralphatg) on CD8 T cells. We found that IL-7Ralpha expression was wholly insufficient for memory CD8 T cell production as it neither increased the total number of cells able to survive from the effector phase nor did it allow the survival of more terminally-differentiated effectors at the expense of genuine memory precursors. To investigate the reason for the why IL-7Ralpha did not affect the CD8 response, we treated mice carrying IL-7RalphatgT cells with IL-7 and found that despite equal expression of the receptor, those cells that were more terminally differentiated were unable to respond with increased survival and proliferation. We have since been able to show that only memory precursors are able to maintain the capability to activate the PI3K/AKT pathway in response to IL-2, IL-7 and IL-15. Furthermore we have shown that by inducing constitutive signaling through the PI3K pathway we are able to significantly reduce the death of effector cells following contraction. Finally, memory CD8 T cell function seems to "mature" with time, after the infection has subsided. We tested whether IL-2 and IL-7 induce this "functional maturation". We found that neither IL-7 nor IL-2 induce functional maturation and that IL-2 actually reduces the proliferative potential of developing CD8 memory T cells. |
