title: Plasmodium-host interactions directly influence the threshold of memory CD8 T cells required for protective immunity.
abstract: 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.
authors: Department of Microbiology, University of Iowa, Iowa City, IA 52242, USA.
authors: Nathan W
authors: NW
authors: Schmidt
authors: Noah S
authors: NS
authors: Butler
authors: John T
authors: JT
authors: Harty
mesh_terms: D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D006790:Host-Parasite Interactions; D007156:Immunologic Memory; D007371:Interferon-gamma / Q000276:immunology; D007376:Interleukin-2 / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA / Q000469:parasitology; D010962:Plasmodium berghei / Q000276:immunology* / Q000528:radiation effects; D010967:Plasmodium yoelii / Q000276:immunology* / Q000528:radiation effects; D015800:Protozoan Proteins / Q000276:immunology*; D034101:Sporozoites / Q000276:immunology*; D016176:T-Lymphocyte Subsets / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology
chemical_list: D007376:Interleukin-2; D015800:Protozoan Proteins; D014409:Tumor Necrosis Factor-alpha; C041595:circumsporozoite protein, Protozoan; D007371:Interferon-gamma