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V gamma 9V delta 2 T cells proliferate in response to phosphoantigens released from erythrocytes infected with asexual and gametocyte stage Plasmodium falciparum
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab. (Ingela Parmryd)
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2018 (Engelska)Ingår i: Cellular Immunology, ISSN 0008-8749, E-ISSN 1090-2163, Vol. 334, s. 11-19Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

V gamma 9V delta 2 T cells, the dominant gamma delta T cell subset in human peripheral blood, are stimulated by phosphoantigens, of which (E)-4-Hydroxy-3-methyl-but-2-enyl pyrophosphate, is produced in the apicoplast of malaria parasites. Cell-free media from synchronised Plasmodium falciparum asexual ring, trophozoite, and schizont stage-cultures of high purity as well as media from ruptured schizont cultures, all stimulated V gamma 9V delta 2 T cell proliferation, as did media from pure gametocyte cultures, whereas media from uninfected erythrocytes cultures did not. The media from ruptured schizont cultures and all the asexual and gametocyte stage cultures contained only background iron levels, suggesting that all erythrocyte haemoglobin is consumed as the parasites develop and supporting that the phosphoantigens were released from intact parasitized erythrocytes. The V gamma 9V delta 2 T cell-stimulating agent was not affected by freezing, thawing or heating but was sensitive to phosphatase treatment, confirming its phosphoantigen identity. In summary, phosphoantigens are released from parasitised erythrocytes at all developmental blood stages.

Ort, förlag, år, upplaga, sidor
2018. Vol. 334, s. 11-19
Nationell ämneskategori
Immunologi inom det medicinska området
Identifikatorer
URN: urn:nbn:se:uu:diva-347678DOI: 10.1016/j.cellimm.2018.08.012ISI: 000450904400002PubMedID: 30177348OAI: oai:DiVA.org:uu-347678DiVA, id: diva2:1195596
Forskningsfinansiär
Vetenskapsrådet, 2010-3258AFA FörsäkringEU, FP7, Sjunde ramprogrammet
Anmärkning

Title in dissertation reference list: Vgamma9Vdelta2 T cells proliferate in response to phosphoantigens released from erythrocytes infected with Plasmodium falciparum at asexual and gametocyte stages

Tillgänglig från: 2018-04-05 Skapad: 2018-04-05 Senast uppdaterad: 2018-12-28Bibliografiskt granskad
Ingår i avhandling
1. Vγ9Vδ2 T cells - response to P. falciparum-derived phosphoantigens and potential for use in colon cancer immunotherapy 
Öppna denna publikation i ny flik eller fönster >>Vγ9Vδ2 T cells - response to P. falciparum-derived phosphoantigens and potential for use in colon cancer immunotherapy 
2018 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
Abstract [en]

Vγ9Vδ2 T cell is the dominant circulating γδ T cell subset in humans, can expand massively upon malaria infection and are cytotoxic to cancer cells. Vγ9Vδ2 T cells are stimulated by phosphoantigens, primarily isoprenoid pyrophosphates like isopentenyl pyrophosphate and (E)-4-hydroxy-3-methyl-but-2-enyl pyrophosphate (HMBPP). Vγ9Vδ2 T cell from human blood were studied for proliferation, response to blood-stage malaria parasites and during colon cancer progression. Vγ9Vδ2 T cell proliferation was stimulated by media from P. falciparum-infected erythrocytes from all asexual blood stages - rings, trophozoites, schizonts and rupturing schizonts as well as sexual stage gametocytes assessed by the protocols we developed to obtain pure cultures of all stages. Further, we demonstrated that the molecules that stimulated the Vγ9Vδ2 T cell proliferation are phosphoantigens that are released from intact infected erythrocytes. This does not require schizont rupture.  Interestingly, the parasites consumed all the iron ion of hemoglobins during their development from the ring to the rupturing schizont stage. We found that an Anopheles gambiae immune cell line responds to HMBPP by activation of MAPK and PI3K signaling pathways. Moreover, transcription of dual oxidase and nitric oxide synthase was upregulated by addition of HMBPP in the midgut of Anopheles gambiae which increases cell tolerance to oxidative stress. A range of small isoprenoid pyrophosphates were found to stimulate proliferation of Vγ9Vδ2 T cells from PBMCs as was the isoprenoid monophosphate DMAP. However other isoprenoid monophosphates and alcohols did not. We found that cryopreserved unexpectedly increase the proliferation ability of HMBPP–stimulated PBMCs. To test the cytotoxicity of Vγ9Vδ2 T cells against adherent colon cancer cell lines, a flow cytometry-based assay was developed. Using the assay we found that proliferated Vγ9Vδ2 T cells are cytotoxcitic to various cancer cells and that HMBPP increases cytotoxicity towards adherent colon cancer cells. In a clinical study we found that Vγ9Vδ2 T cells could not always be proliferated from colon cancer patients and that the inflammatory homing receptor CXCR3 was expressed at higher levels in colon cancer patients than the control group. Moreover, at cancer stadium 4 a lower frequency of Vγ9Vδ2 T cells was more common than in the other groups.

Ort, förlag, år, upplaga, sidor
Uppsala: Acta Universitatis Upsaliensis, 2018. s. 53
Serie
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1455
Nationell ämneskategori
Cell- och molekylärbiologi Immunologi inom det medicinska området
Forskningsämne
Medicinsk cellbiologi
Identifikatorer
urn:nbn:se:uu:diva-347682 (URN)978-91-513-0311-6 (ISBN)
Disputation
2018-05-16, B7:113a, Biomedicum, Husargatan 3, Uppsala, 13:15 (Engelska)
Opponent
Handledare
Tillgänglig från: 2018-04-24 Skapad: 2018-04-05 Senast uppdaterad: 2018-10-08

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Av författaren/redaktören
Liu, ChenxiaoParmryd, Ingela
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Institutionen för medicinsk cellbiologiScience for Life Laboratory, SciLifeLab
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Cellular Immunology
Immunologi inom det medicinska området

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