Protracted Protection to Plasmodium berghei Malaria Is Linked to Functionally and Phenotypically Heterogeneous Liver Memory CD8+ T Cells

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...

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Published in:	The Journal of immunology (1950) Vol. 171; no. 4; pp. 2024 - 2034
Main Authors:	Berenzon, Dmitri, Schwenk, Robert J, Letellier, Lisa, Guebre-Xabier, Mimi, Williams, Jackie, Krzych, Urszula
Format:	Journal Article
Language:	English
Published:	United States Am Assoc Immnol 15-08-2003
Subjects:	Animals Antigens, Protozoan - metabolism Antigens, Protozoan - physiology CD8-Positive T-Lymphocytes - immunology CD8-Positive T-Lymphocytes - metabolism CD8-Positive T-Lymphocytes - parasitology CD8-Positive T-Lymphocytes - transplantation Cell Survival - immunology Female Gamma Rays Hyaluronan Receptors - biosynthesis Immunization Immunologic Memory Immunophenotyping Interferon-gamma - metabolism L-Selectin - biosynthesis Leukocyte Common Antigens - biosynthesis Liver - immunology Liver - parasitology Liver - pathology Malaria - immunology Malaria - pathology Malaria - prevention & control Mice Mice, Inbred C57BL Mice, Knockout Plasmodium berghei - growth & development Plasmodium berghei - immunology Receptors, Interleukin-2 - biosynthesis Sporozoites - immunology Sporozoites - radiation effects T-Lymphocyte Subsets - immunology T-Lymphocyte Subsets - metabolism T-Lymphocyte Subsets - parasitology T-Lymphocyte Subsets - transplantation
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Summary:	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.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0022-1767 1550-6606
DOI:	10.4049/jimmunol.171.4.2024