Cytotoxic CD8(+) T cells recognize and kill Plasmodium vivax-infected reticulocytes

Plasmodium vivax causes approximately 100 million clinical malaria cases yearly(1,2). The basis of protective immunity is poorly understood and thought to be mediated by antibodies(3,4). Cytotoxic CD8(+) T cells (CTLs) protect against other intracellular parasites by detecting parasite peptides presented by Human Leukocyte Antigen Class I (HLA-I) on host cells. CTLs kill parasite-infected mammalian cells and intracellular parasites by releasing their cytotoxic granules(5,6). Perforin (PFN) delivers the antimicrobial peptide granulysin (GNLY) and death-inducing granzymes (Gzm) into the host cell, and GNLY then delivers Gzms into the parasite. CTLs were thought to have no role against Plasmodium spp. blood stages because red blood cells (RBCs) generally do not express HLA-I(7). However, P. vivax infects reticulocytes (Retics) that retain the protein translation machinery. Here we show that P. vivax-infected Retics (iRetic) express HLA-I. Infected patient circulating CD8(+) T cells highly express cytotoxic proteins and recognize and form immunological synapses with iRetics in an HLA-dependent manner, releasing their cytotoxic granules to kill both host cell and intracellular parasite, preventing reinvasion. iRetic and parasite killing is PFN-independent, but depends on GNLY, which generally efficiently forms pores only in microbial membranes(8). We find that P. vivax depletes cholesterol from the iRetic cell membrane, rendering it GNLY-susceptible. This unexpected T cell defense might be mobilized to improve P. vivax vaccine efficacy.