The dissection of CD8 T cells during liver-stage infection

Multiple injections of gamma-radiation-attenuated Plasmodium sporozoites (gamma-spz) can induce long-lived, sterile immunity against pre-erythrocytic stages of malaria. Malaria antigen (Ag)-specific CD8 T cells that produce IFN-gamma are key effector cells in this model of protection. Although there have been numerous reports dealing with gamma-spz-induced CD8 T cells in the spleen, CD8 T cells most likely confer protection by targeting infected hepatocytes. Consequently, in this chapter we discuss observations and hypotheses concerning CD8 T cell responses that occur in the liver after an encounter with the Plasmodium parasite. Protracted protection against pre-erythrocytic stages requires memory CD8 T cells and we discuss evidence that gamma-spz-induced immunity is indeed accompanied by the presence of intrahepatic CD44hi CD45RBlo CD62lo CD122lo effector memory (EM) CD8 T cells and CD44hi CD45RBhi CD621hi CD122hi central memory (CM) CD8 T cells. In addition, the EM CD8 T cells rapidly release IFN-gamma in response to spz challenge. The possible role of Kupffer cells in the processing of spz Ags and the production of cytokines is also considered. Finally, we discuss evidence that is consistent with a model whereby intrahepatic CM CD8 T cells are maintained by IL-15 mediated-homeostatic proliferation while the EM CD8 T cells are conscripted from the CM pool in response to a persisting depot of liver-stage Ag.