Memory CD8 T Cells Specific for Plasmodia Liver-Stage Antigens Maintain Protracted Protection Against Malaria

Abstract

Immunologic memory induced by pathogenic agents or vaccinations is inextricably linked to long-lasting protection. Adequately maintained memory T and B cell pools assure a fast, effective, and specific response against re-infections. Studies of immune responses amongst residents of malaria endemic areas suggest that memory responses to Plasmodia antigens appear to be neither adequately developed nor maintained, because persons who survive episodes of childhood malaria remain vulnerable to persistent or intermittent malaria infections. By contrast, multiple exposures of humans and laboratory rodents to radiation-attenuated Plasmodia sporozoites (γ-spz) induces sterile and long-lasting protection against experimental sporozoite challenge. Protection is associated with MHC-class I-dependent CD8 T cells, the key effectors against pre-erythrocytic stage infection. We have adopted the P. berghei γ-spz mouse model to study memory CD8 T cells that are specific for antigens expressed by Pb liver-stage (LS) parasites and are found predominantly in the liver. On the basis of phenotypic and functional characteristics, we have demonstrated that liver CD8 T cells form two subsets: CD44hiCD62LloKLRG-1+CD107+CD127−CD122loCD8 T effector/effector memory (TE/EM) cells that are the dominant IFN-γ producers and CD44hiCD62LhiKLRG-1−CD107−CD127+CD122hiCD8 T central memory (TCM) cells. In this review, we discuss our observations concerning the role of CD8 TE/EM and CD8 TCM cells in the maintenance of protracted protective immunity against experimental malaria infection. Finally, we present a hypothesis consistent with a model whereby intrahepatic CD8 TCM cells, that are maintained in part by LS-Ag depot and by IL-15-mediated survival and homeostatic proliferation, form a reservoir of cells ready for conscription to CD8 TE/EM cells needed to prevent re-infections.

Trimethoprim-Sulfamethoxazole Prophylaxis During Live Malaria Sporozoite Immunization Induces Long-Lived, Homologous, and Heterologous Protective Immunity Against Sporozoite Challenge

“…The in vivo depletion studies and the immunophenotyping of activated T cells performed with our TMP-SMX chemoprophylaxis vaccination model demonstrate similar immunity to that observed with irradiated sporozoite vaccination [14,28,35,36]. While CS epitope-recognizing CD8 + T cells (effector/ effector memory cells) and the global T-cell response (ie, CD11a hi CD8α cells) are both likely to be important for protection against sporozoite challenge [14,28,[37][38][39], depletion of IFN-γ in our experiments yielded more mixed results, indicating that this cytokine may not be the sole mediator of protection in this model. We cannot rule out the possibility that direct lytic activity of CD8 + T or CD4 + T cells, or CD4 + T-cell mediated help for antibody production, as shown in humans and other rodent models [40], may play some role.…”

In vivo CD8+ T Cell Dynamics in the Liver of Plasmodium yoelii Immunized and Infected Mice

“…The few parasites that do reach the liver are likely opsonized and phagocytozed by Kupffer cells [122], [123]. Should individual sporozoites succeed in infecting hepatocytes, Plasmodium -specific liver resident CD8+ effector memory T cells would likely kill the growing LS before they reach maturity [78], [124]. In agreement with this notion, sporozoite infection of immunized mice resulted in a drastic reduction in LS number compared to naïve mice ( Fig.…”

“…For these reasons, we speculate that other factors, for example cytotoxic effects exerted by proinflammatory cytokines or parasite-specific antibodies some of which are reportedly able to inhibit the intracellular LS development [125], [126], were responsible for the observed reduction in growth rate. While inflammatory cytokines such as IFN-γ are generally thought to eliminate LS via the NO pathway, an intriguing alternative may be that severely growth-inhibited, and thus barely detectable, miniscule parasites persist in the liver of immune mice and contribute to the formation of the depot of LS antigen that is required for maintenance of protracted protective immunity [78].…”

Sterile Immunity to Malaria after DNA Prime/Adenovirus Boost Immunization Is Associated with Effector Memory CD8+T Cells Targeting AMA1 Class I Epitopes

“…CD8+ T lymphocytes are important mediators of protective immunity against the malaria liver stages [3]–[7], killing the intracellular parasites through interferon-gamma (IFN-γ) or release of cytotoxins [8], [9], and thus could provide an effective objective for immunization.…”