γδ T cells suppress Plasmodium falciparum blood-stage infection by direct killing and phagocytosis

Nat Immunol. 2021 Mar;22(3):347-357. doi: 10.1038/s41590-020-00847-4. Epub 2021 Jan 11.

Abstract

Activated Vγ9Vδ2 (γδ2) T lymphocytes that sense parasite-produced phosphoantigens are expanded in Plasmodium falciparum-infected patients. Although previous studies suggested that γδ2 T cells help control erythrocytic malaria, whether γδ2 T cells recognize infected red blood cells (iRBCs) was uncertain. Here we show that iRBCs stained for the phosphoantigen sensor butyrophilin 3A1 (BTN3A1). γδ2 T cells formed immune synapses and lysed iRBCs in a contact, phosphoantigen, BTN3A1 and degranulation-dependent manner, killing intracellular parasites. Granulysin released into the synapse lysed iRBCs and delivered death-inducing granzymes to the parasite. All intra-erythrocytic parasites were susceptible, but schizonts were most sensitive. A second protective γδ2 T cell mechanism was identified. In the presence of patient serum, γδ2 T cells phagocytosed and degraded opsonized iRBCs in a CD16-dependent manner, decreasing parasite multiplication. Thus, γδ2 T cells have two ways to control blood-stage malaria-γδ T cell antigen receptor (TCR)-mediated degranulation and phagocytosis of antibody-coated iRBCs.

Publication types

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

MeSH terms

  • Antigens, CD / metabolism
  • Antigens, Differentiation, T-Lymphocyte / metabolism
  • Antigens, Protozoan / blood
  • Antigens, Protozoan / immunology*
  • Boston
  • Brazil
  • Butyrophilins / metabolism
  • Cells, Cultured
  • Cytotoxicity, Immunologic*
  • Erythrocytes / immunology*
  • Erythrocytes / metabolism
  • Erythrocytes / parasitology
  • Female
  • Granzymes / metabolism
  • Host-Parasite Interactions
  • Humans
  • Immunological Synapses / metabolism
  • Immunological Synapses / parasitology
  • Intraepithelial Lymphocytes / immunology*
  • Intraepithelial Lymphocytes / metabolism
  • Intraepithelial Lymphocytes / parasitology
  • Lymphocyte Activation*
  • Malaria, Falciparum / blood
  • Malaria, Falciparum / immunology*
  • Malaria, Falciparum / parasitology
  • Male
  • Phagocytosis*
  • Plasmodium falciparum / growth & development
  • Plasmodium falciparum / microbiology*

Substances

  • Antigens, CD
  • Antigens, Differentiation, T-Lymphocyte
  • Antigens, Protozoan
  • BTN2A1 protein, human
  • BTN3A1 protein, human
  • Butyrophilins
  • GNLY protein, human
  • GZMB protein, human
  • Granzymes