Hepatic γδ NKT cells modulate liver-resident CD8+ T cells to attenuated malaria parasite vaccines

Plasmodium parasites develop in the liver and egress to infect red blood cells, causing malaria. Vaccines that generate hepatic CD8+ T cells eliminate liver-stage parasites and prevent disease, yet how these T cells are induced is incompletely understood. We report that in mice vaccinated with replication-competent genetically attenuated Plasmodium parasites, antagonism of γδ T cell function curtails protection. Vaccination expands hepatic IFNγ+ γδ NKT cells, and depletion of these cells abrogates hepatic CD8+ T cell responses. IFNγ+ γδ NKT cells are nearly undetectable in the blood at steady state but their frequencies in the periphery are significantly increased following vaccination, hinting at their utility as biomarkers of protection. To assess the relevance of these results in humans, we performed secondary analyses of peripheral blood samples from human clinical trial participants immunized with attenuated Plasmodium parasites (Trial registration: ClinicalTrials.gov NCT01994525 ). Flow cytometric and single cell transcriptomic characterization of γδ T cells in these samples unveil for the first time, increased frequency of activated Vδ2-γδ T cells and gene expression in cytotoxic, tissue-homing Vδ1+ γδ T cells as correlates of protection. Together, these data identify hepatic γδ T cells as targets for the improvement of tissue-resident CD8+ T cell responses against hepatotropic pathogens.