Plasmodium-host interactions directly influence the threshold of memory CD8 T cells required for protective immunity

Plasmodium infections are responsible for millions of cases of malaria and ∼1 million deaths annually. Recently, we showed that sterile protection (95%) in BALB/c mice required Plasmodium berghei circumsporozoite protein (CS(252-260))-specific memory CD8 T cells exceeding a threshold of 1% of all PBLs. Importantly, it is not known if Plasmodium species affect the threshold of CS-specific memory CD8 T cells required for protection. Furthermore, C57BL/6 mice immunized with radiation-attenuated parasites are more difficult to protect against Plasmodium sporozoite challenge than similarly immunized BALB/c mice; however, it is not known whether this is the result of different CD8 T cell specificity, functional attributes of CD8 T cells, or mouse strain-specific factors expressed in nonhematopoietic cells. In this article, we show that more CS-specific memory CD8 T cells are required for protection against P. yoelii sporozoite challenge than for protection against P. berghei sporozoite challenge. Furthermore, P. berghei CS(252)-specific CD8 T cells exhibit reduced protection against P. berghei sporozoite challenge in the context of C57BL/6 and C57BL/10 non-MHC-linked genes in CB6F1 and B10.D2 mice, respectively. Generation and immunization of reciprocal chimeric mice between BALB/c and B10.D2 strains revealed that B10 background factors expressed by nonhematopoietic cells increased the threshold required for protection through a CD8 T cell-extrinsic mechanism. Finally, reduced CS-specific memory CD8 T cell protection in P. yoelii-infected BALB/c or P. berghei-infected B10.D2 mice correlated with increased rates of Plasmodium amplification in the liver. Thus, both Plasmodium species and strain-specific background genes in nonhematopoietic cells determine the threshold of memory CD8 T cells required for protection.