Infectious Sporozoites of Plasmodium berghei Effectively Activate Liver CD8α+ Dendritic Cells

Abstract

Immunization with radiation-attenuated sporozoites (RAS) shown to confer complete sterile protection against Plasmodia liver-stage (LS) infection that lasts about 6 to 9 months in mice. We have found that the intermittent infectious sporozoite challenge to immune mice following RAS vaccination extends the longevity of sterile protection by maintaining CD8+ T cell memory responses to LS infection. It is reported that CD8α+ dendritic cells (DCs) are involved in the induction of LS-specific CD8+ T cells following RAS or genetically attenuated parasite (GAP) vaccination. In this study, we demonstrate that CD8α+ DCs respond differently to infectious sporozoite or RAS inoculation. The higher accumulation and activation of CD8α+ DCs was seen in the liver in response to infectious sporozoite 72 h postinoculation and found to be associated with higher expression of chemokines (CCL-20 and CCL-21) and type I interferon response via toll-like receptor signaling in liver. Moreover, the infectious sporozoites were found to induce qualitative changes in terms of the increased MHCII expression as well as costimulatory molecules including CD40 on the CD8α+ DCs compared to RAS inoculation. We have also found that infectious sporozoite challenge increased CD40L-expressing CD4+ T cells, which could help CD8+ T cells in the liver through “licensing” of the antigen-presenting cells. Our results suggest that infectious sporozoite challenge to prior RAS immunized mice modulates the CD8α+ DCs, which might be shaping the fate of memory CD8+ T cells against Plasmodium LS infection.

Varying Immunizations With Plasmodium Radiation-Attenuated Sporozoites Alter Tissue-Specific CD8+ T Cell Dynamics

“…The increasing involvement of the hepatic CD8 + T cell response might be supported by continuously accumulating, activated dendritic cells at the site of infection, as shown to occur in the course of i.v. RAS immunizations and other infection models ( 23 , 36 – 40 ). Enhanced frequencies of antigen-presenting cells (APC) in the liver might promote the reactivation and build-up of local hepatic CD8 + T cell populations during vaccine-induced secondary and tertiary responses.…”

“…Notably, a recent study reported that the accumulation and activation status of intrahepatic CD8α + DC was significantly increased by i.v. injection of a higher compared to a lower Pb RAS dose ( 40 ).…”

Immune responses to malaria pre‐erythrocytic stages: Implications for vaccine development

“…Liver cells including hepatocytes, liver sinusoidal endothelial cells, Kupffer cells, hepatic DCs and hepatic stellate cells interact with the parasite during the liver invasion process (as reviewed by Hafalla et al 81 ). Rodent studies have shown that CD11c + DCs found in the spleen, liver and liver‐draining lymph nodes are required to present antigens to CD8 + T cells, and their depletion abrogates CD8 + T‐cell responses 5,82‐84 . It is thought that these DCs directly present sporozoite antigens to CD8 + T cells through antigen cross‐presentation 5,8,83 .…”

“…Rodent studies have shown that CD11c + DCs found in the spleen, liver and liver‐draining lymph nodes are required to present antigens to CD8 + T cells, and their depletion abrogates CD8 + T‐cell responses 5,82‐84 . It is thought that these DCs directly present sporozoite antigens to CD8 + T cells through antigen cross‐presentation 5,8,83 . Blocking the ability of the DCs to cross‐present antigens represses CD8 + T‐cell responses 85,86 .…”

“…Blocking the ability of the DCs to cross‐present antigens represses CD8 + T‐cell responses 85,86 . CD4 + T cells play a role in 'licensing' these antigen‐presenting DCs 83,87 . How antigens that are expressed exclusively during EEF development prime CD8 + T‐cell responses remains inadequately characterized.…”