The Threshold of Protection from Liver-Stage Malaria Relies on a Fine Balance between the Number of Infected Hepatocytes and Effector CD8 ⁺ T Cells Present in the Liver

Abstract

Since the demonstration of sterile protection afforded by injection of irradiated sporozoites, CD8 ⁺ T cells have been shown to play a significant role in protection from liver-stage malaria. This is, however, dependent on the presence of an extremely high number of circulating effector cells, thought to be necessary to scan, locate, and kill infected hepatocytes in the short time that parasites are present in the liver. We used an adoptive transfer model to elucidate the kinetics of the effector CD8 ⁺ T cell response in the liver following Plasmodium berghei sporozoite challenge. Although effector CD8 ⁺ T cells require <24 h to find, locate, and kill infected hepatocytes, active migration of Ag-specific CD8 ⁺ T cells into the liver was not observed during the 2-d liver stage of infection, as divided cells were only detected from day 3 postchallenge. However, the percentage of donor cells recruited into division was shown to indicate the level of Ag presentation from infected hepatocytes. By titrating the number of transferred Ag-specific effector CD8 ⁺ T cells and sporozoites, we demonstrate that achieving protection toward liver-stage malaria is reliant on CD8 ⁺ T cells being able to locate infected hepatocytes, resulting in a protection threshold dependent on a fine balance between the number of infected hepatocytes and CD8 ⁺ T cells present in the liver. With such a fine balance determining protection, achieving a high number of CD8 ⁺ T cells will be critical to the success of a cell-mediated vaccine against liver-stage malaria.