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dc.contributor.authorHess, Christopheen
dc.date.accessioned2019-09-27T23:30:31Z
dc.date.available2019-09-27T23:30:31Z
dc.identifier.issn1937-9145
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/297264
dc.description.abstractTGF-beta is produced by tumors, and increased levels are associated with poor survival. Functionally, TGF-beta-mediated suppression of anti-tumor T cell responses contributes to tumor growth and survival. However, TGF-beta can also have tumor suppressive activity, and dissecting cell-type specific molecular effects may decisively inform therapeutic strategies targeting this cytokine. Here we investigated the mechanisms involved in suppression of a key anti-tumor CD4+ T cell function –interferon-gamma (IFN-gamma) production– by tumor-derived TGF-beta in human peripheral and tumor-associated lymphocytes. Suppression required expression and phosphorylation of TGF-beta signaling proteins (Smad proteins), but not their nuclear translocation, and was dependent on oxygen availability –suggesting a metabolic basis. Indeed, Smad proteins were detected in mitochondria of CD4+ T cells, where they were phosphorylated upon TGF-beta exposure. Phosphorylated Smad proteins were also detected ex vivo in mitochondria of tumor-associated lymphocytes. TGF-beta treatment significantly impaired ATP-coupled respiration of CD4+ T cells, and specifically mitochondrial complex V (ATP-Synthase) activity. Finally, inhibition of ATP-Synthase per se was sufficient to impair IFN-gamma production. These results demonstrate that TGF-beta targets T cell metabolism directly, thus diminishing their function (metabolic paralysis), with relevance to human anti-tumor immunity.
dc.description.sponsorshipThis work was supported by the Roche postdoctoral fellowship program and University of Basel research funds (to S.D.) and by Swiss National Science Foundation grants 310030_153059 (to C.H.) and 323530-139181 (to M.F.)
dc.publisherAmerican Association for the Advancement of Science
dc.rightsAll rights reserved
dc.rights.uri
dc.titleTumor-derived TGF-beta inhibits mitochondrial respiration to suppress IFN-gamma production by human CD4+ T cellsen
dc.typeArticle
prism.publicationNameScience Signalingen
dc.identifier.doi10.17863/CAM.44311
dcterms.dateAccepted2019-09-03en
rioxxterms.versionofrecord10.1126/scisignal.aav3334en
rioxxterms.versionAM
rioxxterms.licenseref.urihttp://www.rioxx.net/licenses/all-rights-reserveden
rioxxterms.licenseref.startdate2019-09-03en
rioxxterms.typeJournal Article/Reviewen
cam.issuedOnline2019-09-17en
cam.orpheus.successThu Jan 30 10:37:58 GMT 2020 - Embargo updated*
rioxxterms.freetoread.startdate2019-09-17


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