Abstract
Protection against malaria often decays in the absence of infection, suggesting that protective immunological memory depends on stimulation. Here we have used CD4
+
T cells from a transgenic mouse carrying a T cell receptor specific for a malaria protein, Merozoite Surface Protein-1, to investigate memory in a
Plasmodium chabaudi
infection. CD4
+
memory T cells (CD44
hi
IL-7Rα
+
) developed during the chronic infection, and were readily distinguishable from effector (CD62L
lo
IL-7Rα
−
) cells in acute infection. On the basis of cell surface phenotype, we classified memory CD4
+
T cells into three subsets: central memory, and early and late effector memory cells, and found that early effector memory cells (CD62L
lo
CD27
+
) dominated the chronic infection. We demonstrate a linear pathway of differentiation from central memory to early and then late effector memory cells. In adoptive transfer, CD44
hi
memory cells from chronically infected mice were more effective at delaying and reducing parasitemia and pathology than memory cells from drug-treated mice without chronic infection, and contained a greater proportion of effector cells producing IFN-γ and TNFα, which may have contributed to the enhanced protection. These findings may explain the observation that in humans with chronic malaria, activated effector memory cells are best maintained in conditions of repeated exposure.
Protective immunity against malaria develops only after several infections and can be lost on leaving an area in which malaria is transmitted. This suggests that the chronic infection may maintain the protective immune response. In this paper we have used a mouse model of a blood-stage malaria infection to examine the memory response of CD4
+
T cells during chronic infection. These T cells are required for protective immunity, and also play a part in the inflammatory response that gives rise to malaria disease. Understanding what constitutes a protective CD4
+
T cell may help us design more protective vaccines. We show that these memory CD4
+
T cells persist in an activated state, produce the inflammatory cytokines TNFα and IFN-γ, and are more protective than “resting” memory CD4
+
T cells obtained from mice in which the infection has been eliminated. This may explain why people are better protected against malaria disease when they are infected frequently.
