Protracted Protection to \u3ci\u3ePlasmodium berghei\u3c/i\u3e Malaria Is Linked to Functionally and Phenotypically Heterogeneous Liver Memory CD\u3csup\u3e8+\u3c/sup\u3e T Cells\u3csup\u3e1\u3c/sup\u3e

We previously demonstrated that protection induced by radiation-attenuated (y) Plasmodium berghei sporozoites is linked to MHC class I-restricted CD8+ T cells specific for exoerythrocytic-stage Ags, and that activated intrahepatic memory CD8+ T cells are associated with protracted protection. In this study, we further investigated intrahepatic memory CD8+ T cells to elucidate mechanisms required for their maintenance. Using phenotypic markers indicative of activation (CD44, CD45RB), migration (CD62L), and IFN-y production, we identified two subsets of intrahepatic memory CD8+ T cells: the CD44highCD45RBlowCD62LlowCD122low phenotype, representing the dominant effector memory set, and the CD44highCD45RBhighCD62Llow/highCD122high phenotype, representing the central memory set. Only the effector memory CD8+ T cells responded swiftly to sporozoite challenge by producing sustained IFN-y; the central memory T cells responded with delay, and the IFN-y reactivity was short-lived. In addition, the subsets of liver memory CD8+ T cells segregated according to the expression of CD122 (IL-15R) in that only the central memory CD8+ T cells were CD122high, whereas the effector memory CD8+ T cells were CD122low. Moreover, the effector memory CD8+ T cells declined as protection waned in mice treated with primaquine, a drug that interferes with the formation of liver-stage Ags. We propose that protracted protection induced by P. berghei radiation-attenuated sporozoites depends in part on a network of interactive liver memory CD8+ T cell subsets, each representing a different phase of activation or differentiation, and the balance of which is profoundly affected by the repository of liver-stage Ag and IL-15