Poster Presentation First Malaria World Congress 2018

Liver-resident memory T cells can be harnessed for highly efficient protection against malaria (#285)

Daniel Fernandez-Ruiz 1 , Wei Yi Ng 1 , Lauren Holz 1 , Yik Chun Wong 2 , Vanessa Mollard 3 , Anton Cozijnsen 3 , Nicholas Collins 1 , Szun Szun Tay 2 , David G Bowen 2 , Jonathan H Manton 4 , Friedrich Koch-Nolte 5 , Bjorn Rissiek 5 , Francis R Carbone 1 , Brendan S Crabb 6 , Mireille Lahoud 7 , Ian A Cockburn 8 , Katsuyuki Yui 9 , Scott N Mueller 1 , Patrick Bertolino 2 , Geoffrey I McFadden 3 , Irina Caminschi 7 , William R Heath 1
  1. Peter Doherty Institute, Parkville, VIC, Australia
  2. Centenary Institute, Sydney, New South Wales, Australia
  3. The School of Botany, University of Melbourne, Parkville, Vic, Australia
  4. Department of Electrical and Electronic Engineering, The University of Melbourne, Parkville, VIC, Australia
  5. Institute of Immunology, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany
  6. Macfarlane Burnet Institute of Medical Research, Melbourne, Vic, Australia
  7. Biochemistry and Molecular Biology, Monash University, Clayton, VIC, Australia
  8. Department of Immunology and Infectious Disease, John Curtin School of Medical Research, Canberra, ACT, Australia
  9. Department of Molecular Microbiology and Immunology, Nagasaki University, Nagasaki, Japan

T cell memory allows for the rapid generation of effective immune responses to previously encountered pathogens. Most memory T cells recirculate through the body and require some time to accumulate in tissues upon infection. Since the short duration of the hepatic stage of Plasmodium parasites demands a fast and effective immune response for protection, circulating memory T cells are relatively inefficient at inducing sterile immunity against malaria parasites in the liver. We hypothesized that a newly defined subset of memory T cells, the tissue resident memory T cells (TRM), might be better suited to combat liver-stage malaria parasites: by remaining in the affected tissue after infection is cleared, these cells are capable of eliciting faster, more focused responses than circulating memory T cell subsets upon reinfection. Using transgenic PbT-I cells specific for Plasmodium berghei ANKA (PbA) we found that vaccination with radiation-attenuated PbA sporozoites (RAS) resulted in the generation of a population of PbT-I TRM cells in the liver. These cells constantly surveyed the hepatic sinusoids and were essential for protection, as their depletion rendered vaccinated mice fully susceptible to sporozoite infection. By combining dendritic cell priming and antigen recognition on hepatocytes we generated a novel vaccination strategy, called Prime-and-Trap, that induced the formation of vast numbers of PbT-I TRM in the liver and high levels of sterile protection upon challenge with live sporozoites. Vaccinated mice were resistant to infection with large doses of sporozoites, and protection persisted for more than 200 days. Prime-and-Trap vaccination could be adjusted to promote liver TRM conversion of parasite-specific endogenous CD8 T cells, which also resulted in highly efficient protection. These results show that vaccination aimed at the induction of liver TRM cells is a more effective way to control liver-stage malaria than traditional strategies generating circulating memory T cells.