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dc.contributor.authorThaker, Rajen
dc.contributor.authorSchneider, Helgaen
dc.contributor.authorRudd, Christopheren
dc.date.accessioned2015-04-14T09:39:48Z
dc.date.available2015-04-14T09:39:48Z
dc.date.issued2014-10-23en
dc.identifier.citationThaker YR, Schneider H, Rudd CE, Immunology Letters 2015, 163, 1, 113–119, doi:10.1016/j.imlet.2014.10.020en
dc.identifier.issn0165-2478
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/247318
dc.description.abstractThe transcription factor NF-κB is needed for the induction of inflammatory responses in T-cells. Whether its activation by the antigen-receptor and CD28 is mediated by the same or different intracellular signaling pathways has been unclear. Here, using T-cells from various knock-out (Cd28−/−, adap−/−) and knock-in (i.e. Cd28 Y-170F) mice in conjunction with transfected Jurkat T-cells, we show that the TCR and CD28 use distinct pathways to activate NF-κB in T-cells. Anti-CD28 ligation alone activated NF-κB in primary and Jurkat T-cells as measured by NF-κB reporter and EMSA assays. Anti-CD28 also activated NF-κB normally in primary T-cells from adap−/− mice, while anti-CD3 stimulation required the adaptor ADAP. Over-expression of ADAP or its binding partner SKAP1 failed to enhance anti-CD28 activation of NF-κB, while ADAP greatly increased anti-CD3 induced NF-κB activity. By contrast, CD28 activation of NF-κB depended on GRB-2 binding to CD28 as seen in CD28 deficient Jurkat T-cells reconstituted with the CD28 YMN-FM mutant, and in primary T-cells from CD28 Y170F mutant knock-in mice. CD28 associated with GRB-2, and GRB-2 siRNA impaired CD28 NF-κB activation. GRB-2 binding partner and guanine nucleotide exchange factor, VAV1, greatly enhanced anti-CD28 driven activation of NF-κB. Further, unlike in the case of anti-CD28, NF-κB activation by anti-CD3 and its cooperation with ADAP was strictly dependent on LAT expression. Overall, we provide evidence that CD28 and the TCR complex regulate NF-κB via different signaling modules of GRB-2/VAV1 and LAT/ADAP pathways respectively.
dc.description.sponsorshipThis work was supported by Wellcome Trust Progam Grant (PG) PKAG/504 to Principal Research Fellow (PRF) C.E. Rudd. We are grateful to Oreste Ocuto and Enzo Cerundolo from University of Oxford for providing CHC17 and 1G4 (Cd28−/−) Jurkat cells.
dc.languageEnglishen
dc.language.isoenen
dc.publisherElsevier
dc.rightsAttribution 2.0 UK: England & Wales*
dc.rights.urihttp://creativecommons.org/licenses/by/2.0/uk/*
dc.subjectAdaptorsen
dc.subjectADAPen
dc.subjectVAV-1en
dc.subjectGRB-2en
dc.subjectNF-κBen
dc.titleTCR and CD28 activate the transcription factor NF- B in T-cells viadistinct adaptor signaling complexesen
dc.typeArticle
dc.description.versionThis paper was originally published in Immunology Letters (Thaker YR, Schneider H, Rudd CE, Immunology Letters 2015, 163, 1, 113–119, doi:10.1016/j.imlet.2014.10.020).en
prism.endingPage119
prism.number1en
prism.publicationDate2014en
prism.publicationNameImmunology Lettersen
prism.startingPage113
prism.volume163en
dc.rioxxterms.funderWellcome Trust
dc.rioxxterms.projectidPKAG/504
dcterms.dateAccepted2014-10-15en
rioxxterms.versionofrecord10.1016/j.imlet.2014.10.020en
rioxxterms.licenseref.urihttp://www.rioxx.net/licenses/all-rights-reserveden
rioxxterms.licenseref.startdate2014-10-23en
dc.identifier.eissn1879-0542
rioxxterms.typeJournal Article/Reviewen


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Attribution 2.0 UK: England & Wales
Except where otherwise noted, this item's licence is described as Attribution 2.0 UK: England & Wales