CD8⁺T Cells Eliminate Liver-Stage Plasmodium berghei Parasites without Detectable Bystander Effect

Abstract

bImmunization with attenuated Plasmodium sporozoites or viral vectored vaccines can induce protective CD8 ؉ T cells that can find and eliminate liver-stage malaria parasites. A key question is whether CD8 ؉ T cells must recognize and eliminate each parasite in the liver or whether bystander killing can occur. To test this, we transferred antigen-specific effector CD8؉ T cells to mice that were then coinfected with two Plasmodium berghei strains, only one of which could be recognized directly by the transferred T cells. We found that the noncognate parasites developed normally in these mice, demonstrating that bystander killing of parasites does not occur during the CD8 ؉ T cell response to malaria parasites. Rather, elimination of infected parasites is likely mediated by direct recognition of infected hepatocytes by antigen-specific CD8 ؉ T cells.

Artesunate versus Chloroquine Infection–Treatment–Vaccination Defines Stage-Specific Immune Responses Associated with Prolonged Sterile Protection against Both Pre-erythrocytic and Erythrocytic Plasmodium yoelii Infection

“…Previous studies from our group and others have shown that CD8 + T cells induced by whole parasites are capable of killing Plasmodium-infected hepatocytes in vitro and in vivo (18,30,31). In this study, we determined that ITV-induced liver CD8 + T cells are also capable of interfering with the development of malariainfected hepatocytes in vitro (Fig.…”

“…4). Several mechanisms have been implicated in the killing of infected hepatocytes by CD8 + T cells, including the production of proinflammatory cytokines such as IFN-g and TNF-a, the production of cytotoxic molecules such as perforin and granzyme, and the clustering of CD8 + T cells around infected hepatocytes (18,31,39).…”

“…For example, we have previously shown that contact-dependent killing of infected hepatocytes by CD8 + T cells is a major effector mechanism in BALB/c mice vaccinated with genetically attenuated spz (18). More recently, it has been proposed that CD8 + T cells that interact with infected hepatocytes can recruit both parasite-specific and bystander CD8 + T cells to the proximity of infected hepatocytes, although only parasite-specific CD8 + T cells appear to be involved in killing the infected hepatocytes (30,31).…”

Immunization of Mice with Live-Attenuated Late Liver Stage-Arresting Plasmodium yoelii Parasites Generates Protective Antibody Responses to Preerythrocytic Stages of Malaria

“…For example, animal model studies using whole-parasite vaccines have shown that gamma interferon-positive (IFN-␥ ϩ ) CD8 ϩ T cells are essential for protection of mice against sporozoite challenge and that protection is likely mediated by direct killing of parasite-infected hepatocytes (4)(5)(6)(7)(8)(9)(10). These findings agree with human clinical trial data showing that the level of sporozoite-specific T cells elicited by immunization with wholeparasite malaria vaccines correlates with protection (11)(12)(13)(14).…”

TAP‐mediated processing of exoerythrocytic antigens is essential for protection induced with radiation‐attenuated Plasmodium sporozoites

“…1C). Hence, on the basis of phenotypic expression, immunization of TAP −/− mice with P. berghei RAS did not cause a significant differentiation of CD8 + T cells into CD8 + T EM cells.To resolve whether liver CD8 + T cells from P. berghei RAS immunized mice in both groups represent mainly Ag-specific populations rather than bystander CD8 + T cells [42] recruited by an inflammatory milieu, we adoptively transferred TCR Tg CD8 + T cells specific for the SIINFEKL OVA peptide from OT-1 mice to WT and TAP −/− mice prior to immunization with P. berghei RAS or OVA/Poly (I:C). OT-1 cells expanded in both WT and TAP −/− mice upon immunization with OVA/Poly(I:C), but did not expand in either WT or TAP −/− mice immunized with 75000 P. berghei RAS ( Fig.…”