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

Authors

• Dmitri Berenzon, Walter Reed Army Institute of Research
• Robert J. Schwenk, Walter Reed Army Institute of Research
• Lisa Letellier, Walter Reed Army Institute of Research
• Mimi Guebre-Xabier, Walter Reed Army Institute of Research
• Jackie Williams, Walter Reed Army Institute of Research
• Urszula Krzych, Walter Reed Army Institute of Research

Document Type

Article

Date of this Version

2003

Comments

Published in Journal of Immunology, 171, (2003), pp. 2024-2034

Abstract

We previously demonstrated that protection induced by radiation-attenuated (y) 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-y 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-y; the central memory T cells responded with delay, and the IFN-y 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.