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Infect Immun. 2015 Oct;83(10):3816-24. doi: 10.1128/IAI.00446-15. Epub 2015 Jul 13.

Phosphoantigen Burst upon Plasmodium falciparum Schizont Rupture Can Distantly Activate Vγ9Vδ2 T Cells.

Author information

1
Univ. Bordeaux, CIRID, UMR 5164, Bordeaux, France Centre National de la Recherche Scientifique, CIRID, UMR 5164, Bordeaux, France.
2
Faculty of Infectious and Tropical Diseases, London School of Hygiene & Tropical Medicine, London, United Kingdom.
3
Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, Stockholm, Sweden.
4
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.
5
Institut Pasteur, Immunologie Moléculaire des Parasites, Paris, France.
6
Univ. Bordeaux, CIRID, UMR 5164, Bordeaux, France Centre National de la Recherche Scientifique, CIRID, UMR 5164, Bordeaux, France mmamani@cirid.org.

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.

PMID:
26169273
PMCID:
PMC4567633
DOI:
10.1128/IAI.00446-15
[Indexed for MEDLINE]
Free PMC Article

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