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.
Subject(s)
Antigens, Protozoan/immunology , Cytotoxicity, Immunologic , Erythrocytes/immunology , Intraepithelial Lymphocytes/immunology , Lymphocyte Activation , Malaria, Falciparum/immunology , Phagocytosis , Plasmodium falciparum/microbiology , Antigens, CD/metabolism , Antigens, Differentiation, T-Lymphocyte/metabolism , Antigens, Protozoan/blood , Boston , Brazil , Butyrophilins/metabolism , Cells, Cultured , Erythrocytes/metabolism , Erythrocytes/parasitology , Female , Granzymes/metabolism , Host-Parasite Interactions , Humans , Immunological Synapses/metabolism , Immunological Synapses/parasitology , Intraepithelial Lymphocytes/metabolism , Intraepithelial Lymphocytes/parasitology , Malaria, Falciparum/blood , Malaria, Falciparum/parasitology , Male , Plasmodium falciparum/growth & developmentABSTRACT
NKT cells that express the semi-invariant TCR are innate-like lymphocytes whose functions are regulated by self and foreign glycolipid ligands presented by the Ag-presenting, MHC class I-like molecule CD1d. Activation of NKT cells in vivo results in rapid release of copious amounts of effector cytokines and chemokines with which they regulate innate and adaptive immune responses to pathogens, certain types of cancers, and self-antigens. The nature of CD1d-restricted ligands, the manner in which they are recognized, and the unique effector functions of NKT cells suggest an immunoregulatory role for this T cell subset. Their ability to respond fast and our ability to steer NKT cell cytokine response to altered lipid ligands make them an important target for vaccine design and immunotherapies against autoimmune diseases. This review summarizes our current understanding of CD1d-restricted ligand recognition by NKT cells and how these innate-like lymphocytes regulate inflammation.
