Efficient Development ofPlasmodiumLiver Stage–Specific Memory CD8⁺T Cells during the Course of Blood‐Stage Malarial Infection

Abstract

Immunity to Plasmodium liver stages in individuals in malaria-endemic areas is inextricably linked to concomitant blood-stage parasitemia. Although Plasmodium sporozoite infection induces measurable CD8+ T cell responses, the development of memory T cells during active erythrocytic infection remains uncharacterized. Using transgenic T cells, we assessed antigen-specific effector CD8+ T cell responses induced by normal (NorSpz) and radiation-attenuated (IrrSpz) Plasmodium yoelii sporozoites. The magnitude, phenotypic activation, and differentiation pathway of CD8+ T cells were similarly induced by NorSpz and IrrSpz. Moreover, in normal mice, memory T cells elicited after priming with NorSpz and IrrSpz generated identical recall responses after a heterologous boost strategy. Furthermore, these recall responses exhibited comparable in vivo antiparasite activity. Our results indicate that sporozoites that retain their infective capacity induce memory CD8+ T cells that are robustly recalled by secondary immunization. Thus, erythrocytic infection does not preclude the establishment of memory CD8+ T cell responses to malarial liver stages.

CD8+ T Cells from a Novel T Cell Receptor Transgenic Mouse Induce Liver-Stage Immunity That Can Be Boosted by Blood-Stage Infection in Rodent Malaria

“…It has been reported that blood-stage infection can impair immunity to liver-stage antigens [24], though this is disputed by evidence that there is an equivalent response by liver-stage-specific transgenic T cells to sporozoites in the presence or absence of a subsequent blood-stage infection [32]. To resolve this issue with respect to CD8 + T cell-mediated immunity, we examined the expansion of PbT-I cells after exposing mice to live sporozoites (which will infect the liver then generate blood-stage infection), or irradiated sporozoites alone or followed by blood-stage (iRBC) infection 2 days later, mimicking the time for blood-stage egress after live sporozoite infection ( Figure 9 ).…”

“…Our study extends this concept by indicating that CD8 + T cells of a single specificity for a blood-stage antigen can protect against liver-stage infection when the antigen is also expressed during the liver stage. It has been reported that blood-stage infection can impair immunity to liver-stage antigens [24], though this is disputed by the above study, which uses blood-stage infection to induce anti-sporozoite immunity [25] and by another study that shows an equivalent response by liver-stage-specific transgenic T cells to sporozoites in the presence or absence of a subsequent blood-stage infection [32]. The availability of PbT-I cells will give us the opportunity to examine this relationship when the relevant antigen is expressed during both blood- and liver-stages and to determine how antigens presented during the blood-stage might influence the effector function of T cells capable of recognizing liver-stage antigens.…”

Vaccine‐Like Immunity against Malaria by Repeated Causal‐Prophylactic Treatment of Liver‐StagePlasmodiumParasites

“…Notably, suppressive treatment with chloroquine was intended to exclude potential suppression of immune responses against preerythrocytic-stage parasites by an existing infection with asexual blood-stage parasites. More recently, robust induction of effector and memory CD8 ϩ T cell responses was shown to occur even in the presence of parasites in the erythrocytic cycle [7].Clinical studies of 8-aminoquinolines such as primaquine [8] and tafenoquine [9] for malaria chemoprophylaxis revealed an unusually prolonged delay to the onset of reinfection; in the case of tafenoquine, the delay was Ͼ6 times the plasma half-life. These observations, together with early indications of a protective effect of primaquine treatment [5], led us to hypothesize that repeated pharmacological ablation of liver-stage Plasmodium parasites has the potential to induce strong protective immune responses against sporozoite-induced malaria.…”

“…Notably, suppressive treatment with chloroquine was intended to exclude potential suppression of immune responses against preerythrocytic-stage parasites by an existing infection with asexual blood-stage parasites. More recently, robust induction of effector and memory CD8 ϩ T cell responses was shown to occur even in the presence of parasites in the erythrocytic cycle [7].…”

<i>PLASMODIUM</i> PRE-ERYTHROCYTIC STAGES: BIOLOGY, WHOLE PARASITE VACCINES AND TRANSGENIC MODELS

“…One study reported that the blood stage parasites inhibit Dendritic Cells (DC) function by altering its antigen presentation capacity thus precluding the induction of efficient liver stage immunity (Ocana-Morgner et al, 2003). Using the P. yoelli CSP-TCR transgenic model, an independent study confirmed identical patterns of activation and differentiation of CD8+ T cells following exposure to either normal or radiation attenuated sporozoites (Hafalla et al, 2007). Importantly, the effector and recall responses of memory CD8+ T cells were unaltered in the presence or absence of an ongoing blood stage infection.…”