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.