The role of intrahepatic lymphocytes in mediating protective immunity induced by attenuated Plasmodium berghei sporozoites

Exposure to irradiated Plarmodium sporozoites (y-spz) results in protection against malaria. Like infectious spz, y-spz colonize hepatocytes to underg o maturation. Disruption of liver stage development prevents the generation of protection, which appears, therefore, to depend on liver stage antigens . Although some mechanisms of protection have been identified, they do not include a role for intrahepatic mononuclear cells (MMC). We demonstrated th at P. berghei y-spz-immune murine IHMC adoptively transfer protection to na ive recipients. Characterization of intrahepatic CD4(+) T cells revealed an immediate, albeit transient, response to spz, while the response of CD8(+) T cells is delayed until acquisition of protection. It is presumed that ac tivated CD8(+) T cells home to the Liver to die; y-spz-induced CD8(+)CD45RB (lo)CD44(hi) T cells, however, persist in the liver, but not the spleen, du ring protracted protection. The association between CD8(+)CD45RB(lo)CD44(hi ) T cells and protection has been verified using MHC class I and CD1 knocko ut mice and mice with disrupted liver stage parasites. Based on kinetic stu dies, we propose that interferon-gamma, presumably released by intrahepatic effector CD8(+) Tcells, mediates protection; the persistence of CD8(+) T c ells is, in turn, linked to Plasmodium antigen depots and cytokines release d by CD4(+) T cells and/or NK T cells.