Prolonged Antigen Presentation Is Required for Optimal CD8+ T Cell Responses against Malaria Liver Stage Parasites

Abstract

Immunization with irradiated sporozoites is currently the most effective vaccination strategy against liver stages of malaria parasites, yet the mechanisms underpinning the success of this approach are unknown. Here we show that the complete development of protective CD8+ T cell responses requires prolonged antigen presentation. Using TCR transgenic cells specific for the malaria circumsporozoite protein, a leading vaccine candidate, we found that sporozoite antigen persists for over 8 weeks after immunization—a remarkable finding since irradiated sporozoites are incapable of replication and do not differentiate beyond early liver stages. Persisting antigen was detected in lymphoid organs and depends on the presence of CD11c+ cells. Prolonged antigen presentation enhanced the magnitude of the CD8+ T cell response in a number of ways. Firstly, reducing the time primed CD8+ T cells were exposed to antigen in vivo severely reduced the final size of the developing memory population. Secondly, fully developed memory cells expanded in previously immunized mice but not when transferred to naïve animals. Finally, persisting antigen was able to prime naïve cells, including recent thymic emigrants, to become functional effector cells capable of eliminating parasites in the liver. Together these data show that the optimal development of protective CD8+ T cell immunity against malaria liver stages is dependent upon the prolonged presentation of sporozoite-derived antigen.

In vivo imaging of CD8+T cell-mediated elimination of malaria liver stages

“…Cluster formation during Plasmodium infection may, however, require the presence of large numbers of preexisting specific T cells (19). Such a large number may only be induced by vaccination with subunit vaccines or immunogens such as RAS, which have been shown to provide depots of persisting antigen that may help induce and maintain CD8 + T-cell responses of broad specificity (20).…”

Induction of Antimalaria Immunity by Pyrimethamine Prophylaxis during Exposure to Sporozoites Is Curtailed by Parasite Resistance

“…Using these attenuation protocols, sporozoites are able to glide and invade, but growth arrest occurs at a relatively early stage during liverstage development. Intrahepatic development of malaria parasites is a prerequisite for allowing the immune system to mount protective responses, since heat-killed sporozoites that cannot invade hepatocytes do not elicit robust protection against sporozoite challenge (12,19,37). In contrast, attenuation by pyrimethamine permits hepatocyte invasion but appears to block intrahepatocytic replication ( Fig.…”

Differential Kinetics of Antigen Dependency of CD4+ and CD8+ T Cells

“…However, there is also data that CD8 + T cell expansion is correlated with the continued duration of TCR stimulation in the context of both infections and sterile vaccinations (13)(14)(15)(16)(17)(18)(19)(20)(21). The reason for this discrepancy is currently unclear and cannot be explained by differences of protocol, experimental systems or availability of help or inflammation.…”