title: Long term protection after immunization with P. berghei sporozoites correlates with sustained IFNγ responses of hepatic CD8+ memory T cells.
abstract: Protection against P. berghei malaria can successfully be induced in mice by immunization with both radiation attenuated sporozoites (RAS) arresting early during liver stage development, or sporozoites combined with chloroquine chemoprophylaxis (CPS), resulting in complete intra-hepatic parasite development before killing of blood-stages by chloroquine takes place. We assessed the longevity of protective cellular immune responses by RAS and CPS P. berghei immunization of C57BL/6j mice. Strong effector and memory (T(EM)) CD8+ T cell responses were induced predominantly in the liver of both RAS and CPS immunized mice while CD4+ T cells with memory phenotype remained at base line levels. Compared to unprotected naïve mice, we found high sporozoite-specific IFNγ ex vivo responses that associated with induced levels of in vivo CD8+ T(EM) cells in the liver but not spleen. Long term evaluation over a period of 9 months showed a decline of malaria-specific IFNγ responses in RAS and CPS mice that significantly correlated with loss of protection (r(2) = 0.60, p<0.0001). The reducing IFNγ response by hepatic memory CD8+ T cells could be boosted by re-exposure to wild-type sporozoites. Our data show that sustainable protection against malaria associates with distinct intra-hepatic immune responses characterized by strong IFNγ producing CD8+ memory T cells.
authors.affiliation: Department of Medical Microbiology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands. r.sauerwein@mmb.umcn.nl
authors.forename: Krystelle
authors.initials: K
authors.lastname: Nganou-Makamdop
authors.forename: Geert-Jan
authors.initials: GJ
authors.lastname: van Gemert
authors.forename: Theo
authors.initials: T
authors.lastname: Arens
authors.forename: Cornelus C
authors.initials: CC
authors.lastname: Hermsen
authors.forename: Robert W
authors.initials: RW
authors.lastname: Sauerwein
mesh_terms: D000818:Animals; D000913:Antibodies, Protozoan / Q000276:immunology; D000962:Antimalarials / Q000494:pharmacology; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D002478:Cells, Cultured; D002738:Chloroquine / Q000494:pharmacology; D003131:Combined Modality Therapy; D005260:Female; D005434:Flow Cytometry; D007114:Immunization; D007156:Immunologic Memory / Q000276:immunology; D007371:Interferon-gamma / Q000276:immunology* / Q000378:metabolism; D008099:Liver / Q000276:immunology / Q000469:parasitology; D008288:Malaria / Q000188:drug therapy / Q000276:immunology / Q000469:parasitology; D017780:Malaria Vaccines / Q000008:administration & dosage / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D010962:Plasmodium berghei / Q000187:drug effects / Q000276:immunology*; D013154:Spleen / Q000276:immunology / Q000469:parasitology; D034101:Sporozoites / Q000276:immunology*; D013997:Time Factors
chemical_list: D000913:Antibodies, Protozoan; D000962:Antimalarials; D017780:Malaria Vaccines; D007371:Interferon-gamma; D002738:Chloroquine