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

Nat Med. 2018 Sep;24(9):1330-1336. doi: 10.1038/s41591-018-0117-4. Epub 2018 Jul 23.

Abstract

Plasmodium vivax causes approximately 100 million clinical malaria cases yearly1,2. The basis of protective immunity is poorly understood and thought to be mediated by antibodies3,4. Cytotoxic CD8+ T cells protect against other intracellular parasites by detecting parasite peptides presented by human leukocyte antigen class I on host cells. Cytotoxic CD8+ T cells kill parasite-infected mammalian cells and intracellular parasites by releasing their cytotoxic granules5,6. Perforin delivers the antimicrobial peptide granulysin and death-inducing granzymes into the host cell, and granulysin then delivers granzymes into the parasite. Cytotoxic CD8+ T cells were thought to have no role against Plasmodium spp. blood stages because red blood cells generally do not express human leukocyte antigen class I7. However, P. vivax infects reticulocytes that retain the protein translation machinery. Here we show that P. vivax-infected reticulocytes express human leukocyte antigen class I. Infected patient circulating CD8+ T cells highly express cytotoxic proteins and recognize and form immunological synapses with P. vivax-infected reticulocytes in a human leukocyte antigen-dependent manner, releasing their cytotoxic granules to kill both host cell and intracellular parasite, preventing reinvasion. P. vivax-infected reticulocytes and parasite killing is perforin independent, but depends on granulysin, which generally efficiently forms pores only in microbial membranes8. We find that P. vivax depletes cholesterol from the P. vivax-infected reticulocyte cell membrane, rendering it granulysin-susceptible. This unexpected T cell defense might be mobilized to improve P. vivax vaccine efficacy.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antigens, Differentiation, T-Lymphocyte / metabolism
  • CD8-Positive T-Lymphocytes / immunology*
  • Cytotoxicity, Immunologic*
  • Female
  • HLA Antigens / metabolism
  • Humans
  • Lymphocyte Activation / immunology
  • Lymphocyte Count
  • Malaria / blood
  • Male
  • Plasmodium vivax / physiology*
  • Reticulocytes / parasitology*
  • Reticulocytes / ultrastructure

Substances

  • Antigens, Differentiation, T-Lymphocyte
  • GNLY protein, human
  • HLA Antigens