Cellular and molecular requirements for the recall of IL-4-producing memory CD4+CD45RO+CD27- T cells during protection induced by attenuated Plasmodium falciparum sporozoites

Abstract

The requirements for maintenance of antigen (Ag)-specific memory T cells in protection to malaria is poorly understood. We have previously demonstrated a recall of IL-4-producing memory CD4+CD45RO+ T cells with parasitized red blood cells (pRBC) in persons protected by radiation-attenuated Plasmodium falciparum sporozoites (γ-spz). Using the CD27 marker, we have now identified two subsets of CD4+CD45RO+ T cells: CD4+CD45RO+CD27+ T cells representing an early memory and CD4+CD45RO+CD27- T cells representing a terminally differentiated memory cells. A small subset of CD4+CD45RO+CD27- T cells also expressed CD70, the CD27 ligand. The addition of anti-CD70 monoclonal antibody (mAb) to pRBC-stimulated cultures significantly inhibited the conversion of CD27+ to CD27- subset without profoundly affecting IL-4 production. In contrast, the inclusion of anti-CD27 mAb in parallel cultures abrogated IL-4 production without interfering with conscription of T cells into the CD27- T cell set. We propose that the persistence of memory CD4+ T cells depends on Ag-driven conscription of a mature memory phenotype through co-ligation of CD27 and CD70 expressed, respectively, on CD27+ and CD27- T cells. Hence, protracted protection in malaria depends in part on memory CD4+ T cells that require specific Ag presumably from the repositories of liver-and blood-stage antigens and the delivery of a second signal from the CD27:CD70 interaction.