Plasmodium cellular effector mechanisms and the hepatic microenvironment - PubMed (original) (raw)

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Plasmodium cellular effector mechanisms and the hepatic microenvironment

Ute Frevert et al. Front Microbiol. 2015.

Abstract

Plasmodium falciparum malaria remains one of the most serious health problems globally. Immunization with attenuated parasites elicits multiple cellular effector mechanisms capable of eliminating Plasmodium liver stages. However, malaria liver stage (LS) immunity is complex and the mechanisms effector T cells use to locate the few infected hepatocytes in the large liver in order to kill the intracellular LS parasites remain a mystery to date. Here, we review our current knowledge on the behavior of CD8 effector T cells in the hepatic microvasculature, in malaria and other hepatic infections. Taking into account the unique immunological and lymphogenic properties of the liver, we discuss whether classical granule-mediated cytotoxicity might eliminate infected hepatocytes via direct cell contact or whether cytokines might operate without cell-cell contact and kill Plasmodium LSs at a distance. A thorough understanding of the cellular effector mechanisms that lead to parasite death hence sterile protection is a prerequisite for the development of a successful malaria vaccine to protect the 40% of the world's population currently at risk of Plasmodium infection.

Keywords: CD8 T cells; Plasmodium; antigen-presenting cells; liver; liver lymphatics.

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Figures

FIGURE 1

FIGURE 1

Immunological implications of the hepatic blood-lymph countercurrent. (A) The liver generates lymph by filtering blood plasma (small red arrows) through the sieve plates of the sinusoidal endothelial cells (LSEC) into the perisinusoidal space of Disse formed by LSECs and hepatocytes. The lymph (green arrows) flows inside the space of Disse around the perisinusoidal stellate cells (SC) toward the portal field, while the blood (red arrows) continues its path in the opposite direction, from the portal venule (PV) to the central venule (CV). (B) LSECs represent the blood-lymph barrier of the liver: they express both the vascular marker PECAM-1 (red) and the lymphatic marker LYVE-1 (green). The two markers are depicted separately for clarity.

FIGURE 2

FIGURE 2

Model for Plasmodium antigen presentation in the liver. (A) Sporozoites continuously release antigens such as CSP and TRAP from their surface. On their way from the sinusoidal lumen into the liver parenchyma, sporozoites glide along LSECs, traverse KCs, and migrate through several hepatocytes before infecting a final one (red line). In naïve mice, contact-mediated translocation of sporozoite antigens into the cytoplasm of these liver cells may result in antigen presentation by LSECs, KCs, as well as traversed and infected hepatocytes (red outline). (B) Sporozoite infection of naïve mice should allow late-LS antigen expression exclusively on infected hepatocytes, i.e., those cells in which the parasites develop (red outline). (C) During repeated exposure to viable sporozoites or multiple rounds of immunization with attenuated parasites, infected hepatocytes die after completion of LS development, resulting in the release of debris and leftover late-LS antigens into the environment. These late-LS antigens may then be internalized by nearby APCs such as LSECs and KCs and cross-presented to CD8 effector T cells monitoring the liver. (D) Of the various DC subsets that are involved in inflammatory processes of the liver, the conventional CD8α+DCs are required for the CD8 T cell-mediated elimination of Plasmodium LS. While their exact location in the liver is unknown, Plasmodium infection likely attracts immature cCD8α+DCs to the hepatic sinusoids, where they interact with KCs and acquire sporozoite antigens. Extravasation into the space of Disse would allow these DCs (blue) to communicate with CD8 effector T cells patrolling the sinusoids. DCs may also internalize cellular and parasite debris released from dead infected hepatocytes and subsequently cross-present these antigens to CD8 effector T cells, either from within the space of Disse or after traveling to the LNs that drain the liver.

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