title: Protracted protection to Plasmodium berghei malaria is linked to functionally and phenotypically heterogeneous liver memory CD8+ T cells.
abstract: We previously demonstrated that protection induced by radiation-attenuated (gamma) Plasmodium berghei sporozoites is linked to MHC class I-restricted CD8(+) T cells specific for exoerythrocytic-stage Ags, and that activated intrahepatic memory CD8(+) T cells are associated with protracted protection. In this study, we further investigated intrahepatic memory CD8(+) T cells to elucidate mechanisms required for their maintenance. Using phenotypic markers indicative of activation (CD44, CD45RB), migration (CD62L), and IFN-gamma production, we identified two subsets of intrahepatic memory CD8(+) T cells: the CD44(high)CD45RB(low)CD62L(low)CD122(low) phenotype, representing the dominant effector memory set, and the CD44(high)CD45RB(high)CD62L(low/high)CD122(high) phenotype, representing the central memory set. Only the effector memory CD8(+) T cells responded swiftly to sporozoite challenge by producing sustained IFN-gamma; the central memory T cells responded with delay, and the IFN-gamma reactivity was short-lived. In addition, the subsets of liver memory CD8(+) T cells segregated according to the expression of CD122 (IL-15R) in that only the central memory CD8(+) T cells were CD122(high), whereas the effector memory CD8(+) T cells were CD122(low). Moreover, the effector memory CD8(+) T cells declined as protection waned in mice treated with primaquine, a drug that interferes with the formation of liver-stage Ags. We propose that protracted protection induced by P. berghei radiation-attenuated sporozoites depends in part on a network of interactive liver memory CD8(+) T cell subsets, each representing a different phase of activation or differentiation, and the balance of which is profoundly affected by the repository of liver-stage Ag and IL-15.
authors.affiliation: Department of Immunology and Entomology, Walter Reed Army Institute of Research, Silver Spring, MD 20910, USA.
authors.forename: Dmitri
authors.initials: D
authors.lastname: Berenzon
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Schwenk
authors.forename: Lisa
authors.initials: L
authors.lastname: Letellier
authors.forename: Mimi
authors.initials: M
authors.lastname: Guebre-Xabier
authors.forename: Jackie
authors.initials: J
authors.lastname: Williams
authors.forename: Urszula
authors.initials: U
authors.lastname: Krzych
mesh_terms: D000818:Animals; D000953:Antigens, Protozoan / Q000378:metabolism / Q000502:physiology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism* / Q000469:parasitology / Q000637:transplantation; D002470:Cell Survival / Q000276:immunology; D005260:Female; D005720:Gamma Rays; D018960:Hyaluronan Receptors / Q000096:biosynthesis; D007114:Immunization; D007156:Immunologic Memory; D016130:Immunophenotyping; D007371:Interferon-gamma / Q000378:metabolism; D019041:L-Selectin / Q000096:biosynthesis; D017493:Leukocyte Common Antigens / Q000096:biosynthesis; D008099:Liver / Q000276:immunology* / Q000469:parasitology / Q000473:pathology; D008288:Malaria / Q000276:immunology* / Q000473:pathology / Q000517:prevention & control*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010962:Plasmodium berghei / Q000254:growth & development / Q000276:immunology*; D015375:Receptors, Interleukin-2 / Q000096:biosynthesis; D034101:Sporozoites / Q000276:immunology / Q000528:radiation effects; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism / Q000469:parasitology / Q000637:transplantation
chemical_list: D000953:Antigens, Protozoan; D018960:Hyaluronan Receptors; D015375:Receptors, Interleukin-2; D019041:L-Selectin; D007371:Interferon-gamma; D017493:Leukocyte Common Antigens