title: Phosphoantigen Burst upon Plasmodium falciparum Schizont Rupture Can Distantly Activate Vγ9Vδ2 T Cells.
abstract: Malaria induces potent activation and expansion of the Vγ9Vδ2 subpopulation of γδT cells, which inhibit the Plasmodium falciparum blood cycle through soluble cytotoxic mediators, abrogating merozoite invasion capacity. Intraerythrocytic stages efficiently trigger Vγ9Vδ2 T-cell activation and degranulation through poorly understood mechanisms. P. falciparum blood-stage extracts are known to contain phosphoantigens able to stimulate Vγ9Vδ2 T cells, but how these are presented by intact infected red blood cells (iRBCs) remains elusive. Here we show that, unlike activation by phosphoantigen-expressing cells, Vγ9Vδ2 T-cell activation by intact iRBCs is independent of butyrophilin expression by the iRBC, and contact with an intact iRBC is not required. Moreover, blood-stage culture supernatants proved to be as potent activators of Vγ9Vδ2 T cells as iRBCs. Bioactivity in the microenvironment is attributable to phosphoantigens, as it is dependent on the parasite DOXP pathway, on Vγ9Vδ2 TCR signaling, and on butyrophilin expression by Vγ9Vδ2 T cells. Kinetic studies showed that the phosphoantigens were released at the end of the intraerythrocytic cycle at the time of parasite egress. We document exquisite sensitivity of Vγ9Vδ2 T cells, which respond to a few thousand parasites. These data unravel a novel framework, whereby release of phosphoantigens into the extracellular milieu by sequestered parasites likely promotes activation of distant Vγ9Vδ2 T cells that in turn exert remote antiparasitic functions.
authors.affiliation: Univ. Bordeaux, CIRID, UMR 5164, Bordeaux, France Centre National de la Recherche Scientifique, CIRID, UMR 5164, Bordeaux, France.
authors.forename: Marianne
authors.initials: M
authors.lastname: Guenot
authors.affiliation: Univ. Bordeaux, CIRID, UMR 5164, Bordeaux, France Centre National de la Recherche Scientifique, CIRID, UMR 5164, Bordeaux, France.
authors.forename: Séverine
authors.initials: S
authors.lastname: Loizon
authors.affiliation: Univ. Bordeaux, CIRID, UMR 5164, Bordeaux, France Centre National de la Recherche Scientifique, CIRID, UMR 5164, Bordeaux, France.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Howard
authors.affiliation: Univ. Bordeaux, CIRID, UMR 5164, Bordeaux, France Centre National de la Recherche Scientifique, CIRID, UMR 5164, Bordeaux, France.
authors.forename: Giulia
authors.initials: G
authors.lastname: Costa
authors.affiliation: Faculty of Infectious and Tropical Diseases, London School of Hygiene & Tropical Medicine, London, United Kingdom.
authors.forename: David A
authors.initials: DA
authors.lastname: Baker
authors.affiliation: Univ. Bordeaux, CIRID, UMR 5164, Bordeaux, France Centre National de la Recherche Scientifique, CIRID, UMR 5164, Bordeaux, France.
authors.forename: Shaneel Y
authors.initials: SY
authors.lastname: Mohabeer
authors.affiliation: Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, Stockholm, Sweden.
authors.forename: Marita
authors.initials: M
authors.lastname: Troye-Blomberg
authors.affiliation: Univ. Bordeaux, CIRID, UMR 5164, Bordeaux, France Centre National de la Recherche Scientifique, CIRID, UMR 5164, Bordeaux, France CHU de Bordeaux, Immunology and Immunogenetic Laboratory, Bordeaux, France.
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Moreau
authors.affiliation: Univ. Bordeaux, CIRID, UMR 5164, Bordeaux, France Centre National de la Recherche Scientifique, CIRID, UMR 5164, Bordeaux, France.
authors.forename: Julie
authors.initials: J
authors.lastname: Déchanet-Merville
authors.affiliation: Institut Pasteur, Immunologie Moléculaire des Parasites, Paris, France.
authors.forename: Odile
authors.initials: O
authors.lastname: Mercereau-Puijalon
authors.affiliation: Univ. Bordeaux, CIRID, UMR 5164, Bordeaux, France Centre National de la Recherche Scientifique, CIRID, UMR 5164, Bordeaux, France mmamani@cirid.org.
authors.forename: Maria
authors.initials: M
authors.lastname: Mamani-Matsuda
authors.affiliation: Univ. Bordeaux, CIRID, UMR 5164, Bordeaux, France Centre National de la Recherche Scientifique, CIRID, UMR 5164, Bordeaux, France.
authors.forename: Charlotte
authors.initials: C
authors.lastname: Behr
mesh_terms: D000953:Antigens, Protozoan / Q000276:immunology* / Q000378:metabolism; D004912:Erythrocytes / Q000469:parasitology; D006801:Humans; D008213:Lymphocyte Activation; D016778:Malaria, Falciparum / Q000276:immunology* / Q000469:parasitology; D052940:Merozoites / Q000254:growth & development / Q000276:immunology / Q000502:physiology; D010766:Phosphorylation; D010963:Plasmodium falciparum / Q000254:growth & development / Q000276:immunology* / Q000502:physiology; D015800:Protozoan Proteins / Q000276:immunology* / Q000378:metabolism; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000469:parasitology
chemical_list: D000953:Antigens, Protozoan; D015800:Protozoan Proteins