title: Differential effector pathways regulate memory CD8 T cell immunity against Plasmodium berghei versus P. yoelii sporozoites.
abstract: Malaria results in >1,000,000 deaths per year worldwide. Although no licensed vaccine exists, much effort is currently focused on subunit vaccines that elicit CD8 T cell responses directed against Plasmodium parasite liver stage Ags. Multiple immune-effector molecules play a role in antimicrobial immunity mediated by memory CD8 T cells, including IFN-gamma, perforin, TRAIL, Fas ligand, and TNF-alpha. However, it is not known which pathways are required for memory CD8 T cell-mediated immunity against liver stage Plasmodium infection. In this study, we used a novel immunization strategy to generate memory CD8 T cells in the BALB/c mouse model of P. berghei or P. yoelii sporozoite infection to examine the role of immune-effector molecules in resistance to the liver stage infection. Our studies reveal that endogenous memory CD8 T cell-mediated protection against both parasite species is, in part, dependent on IFN-gamma, whereas perforin was only critical in protection against P. yoelii. We further show that neutralization of TNF-alpha in immunized mice markedly reduces memory CD8 T cell-mediated protection against both parasite species. Thus, our studies identify IFN-gamma and TNF-alpha as important components of the noncytolytic pathways that underlie memory CD8 T cell-mediated immunity against liver stage Plasmodium infection. Our studies also show that the effector pathways that memory CD8 T cells use to eliminate liver stage infection are, in part, Plasmodium species specific.
authors.affiliation: Department of Microbiology, University of Iowa, Iowa City, IA 52242, USA.
authors.forename: Noah S
authors.initials: NS
authors.lastname: Butler
authors.forename: Nathan W
authors.initials: NW
authors.lastname: Schmidt
authors.forename: John T
authors.initials: JT
authors.lastname: Harty
mesh_terms: D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D009033:Culicidae / Q000469:parasitology; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism; D053222:Fas Ligand Protein / Q000276:immunology / Q000378:metabolism; D005260:Female; D007156:Immunologic Memory / Q000276:immunology; D007371:Interferon-gamma / Q000172:deficiency / Q000235:genetics / Q000276:immunology; D008089:Listeria monocytogenes / Q000276:immunology; D008109:Liver Diseases, Parasitic / Q000276:immunology / Q000469:parasitology; D008288:Malaria / Q000276:immunology* / Q000469:parasitology / Q000517:prevention & control; D017780:Malaria Vaccines / Q000008:administration & dosage / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D054353:Perforin / Q000172:deficiency / Q000235:genetics / Q000276:immunology; D010962:Plasmodium berghei / Q000276:immunology*; D010967:Plasmodium yoelii / Q000276:immunology*; D015398:Signal Transduction / Q000276:immunology; D034101:Sporozoites / Q000276:immunology*; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000172:deficiency / Q000235:genetics / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology / Q000378:metabolism
chemical_list: D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D017780:Malaria Vaccines; D053221:TNF-Related Apoptosis-Inducing Ligand; C505654:Tnfsf10 protein, mouse; D014409:Tumor Necrosis Factor-alpha; D054353:Perforin; D007371:Interferon-gamma