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Protracted Protection to Plasmodium berghei Malaria Is Linked to Functionally and Phenotypically Heterogeneous Liver Memory CD8⁺ T Cells¹

Dmitri Berenzon^*, Robert J. Schwenk^*, Lisa Letellier^*, Mimi Guebre-Xabier^2,*, Jackie Williams and Urszula Krzych^3,*

Departments of ^* Immunology and Entomology, Division of Communicable Diseases and Immunology, Walter Reed Army Institute of Research, Silver Spring, MD 20910

We previously demonstrated that protection induced by radiation-attenuated () 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- production, we identified two subsets of intrahepatic memory CD8⁺ T cells: the CD44^highCD45RB^lowCD62L^lowCD122^low phenotype, representing the dominant effector memory set, and the CD44^highCD45RB^highCD62L^low/highCD122^high phenotype, representing the central memory set. Only the effector memory CD8⁺ T cells responded swiftly to sporozoite challenge by producing sustained IFN-; the central memory T cells responded with delay, and the IFN- 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.

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