Nonspecific CD8 T Cells and Dendritic Cells/Macrophages Participate in Formation of CD8 T Cell-Mediated Clusters against Malaria Liver-Stage Infection.

CD8 T cells are the major effector cells that protect against malaria liver-stage infection, forming clusters around -infected hepatocytes and eliminating parasites after a prolonged interaction with these hepatocytes. We aimed to investigate the roles of specific and nonspecific CD8 T cells in cluster formation and protective immunity. To this end, we used ANKA expressing ovalbumin as well as CD8 T cells from transgenic mice expressing a T cell receptor specific for ovalbumin (OT-I) and CD8 T cells specific for an unrelated antigen, respectively. While antigen-specific CD8 T cells were essential for cluster formation, both antigen-specific and nonspecific CD8 T cells joined the clusters. However, nonspecific CD8 T cells did not significantly contribute to protective immunity. In the livers of infected mice, specific CD8 T cells expressed high levels of CD25, compatible with a local, activated effector phenotype. imaging of the liver revealed that specific CD8 T cells interact with CD11c cells around infected hepatocytes. The depletion of CD11c cells virtually eliminated the clusters in the liver, leading to a significant decrease in protection. These experiments reveal an essential role of hepatic CD11c dendritic cells and presumably macrophages in the formation of CD8 T cell clusters around -infected hepatocytes. Once cluster formation is triggered by parasite-specific CD8 T cells, specific and unrelated activated CD8 T cells join the clusters in a chemokine- and dendritic cell-dependent manner. Nonspecific CD8 T cells seem to play a limited role in protective immunity against parasites.