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dc.contributor.authorVolkov, Yuri
dc.contributor.authorKelleher, Dermot
dc.contributor.authorLong, Aideen
dc.contributor.authorFallon, Padraic
dc.contributor.authorVerma, Navin K.
dc.contributor.authorDempsey, Eugene
dc.contributor.authorDavies, Anthony
dc.contributor.authorBarry, Sean P.
dc.date.accessioned2019-11-21T10:47:27Z
dc.date.available2019-11-21T10:47:27Z
dc.date.issued2012
dc.date.submitted2012en
dc.identifier.citationVerma, N.K., Dempsey, E., Long, A., Davies, A., Barry, S.P., Fallon, P.G., Volkov, Y. & Kelleher, D., Leukocyte function-associated antigen-1/intercellular adhesion molecule-1 interaction induces a novel genetic signature resulting in T-cells refractory to transforming growth factor-β signaling., 2012, The Journal of biological chemistry, 287, 32en
dc.identifier.otherY
dc.identifier.urihttp://www.jbc.org/content/287/32/27204
dc.identifier.urihttp://hdl.handle.net/2262/90814
dc.description.abstractThe immunesuppressive cytokine TGF-β plays crucial regulatory roles in the induction and maintenance of immunologic tolerance and prevention of immunopathologies. However, it remains unclear how circulating T-cells can escape from the quiescent state maintained by TGF-β. Here, we report that the T-cell integrin leukocyte function-associated antigen-1 (LFA-1) interaction with its ligand intercellular adhesion molecule-1 (ICAM-1) induces a genetic signature associated with reduced TGF-β responsiveness via up-regulation of SKI, E3 ubiquitin-protein ligase SMURF2, and SMAD7 (mothers against decapentaplegic homolog 7) genes and proteins. We confirmed that the expression of these TGF-β inhibitory molecules was dependent on STAT3 and/or JNK activation. Increased expression of SMAD7 and SMURF2 in LFA-1/ICAM-1 cross-linked T-cells resulted in impaired TGF-β-mediated phosphorylation of SMAD2 and suppression of IL-2 secretion. Expression of SKI caused resistance to TGF-β-mediated suppression of IL-2, but SMAD2 phosphorylation was unaffected. Blocking LFA-1 by neutralizing antibody or specific knockdown of TGF-β inhibitory molecules by siRNA substantially restored LFA-1/ICAM-1-mediated alteration in TGF-β signaling. LFA-1/ICAM-1-stimulated human and mouse T-cells were refractory to TGF-β-mediated induction of FOXP3+ (forkhead box P3) and RORγt+ (retinoic acid-related orphan nuclear receptor γt) Th17 differentiation. These mechanistic data suggest an important role for LFA-1/ICAM-1 interactions in immunoregulation concurrent with lymphocyte migration that may have implications at the level of local inflammatory response and for anti-LFA-1-based therapies.en
dc.description.sponsorshipThis work was supported by grants from the Enterprise Ireland, Higher Education Authority of Ireland under the Program for Research in Third Level Institutions (PRTLI) Cycle 3, Science Foundation Ireland (SFI), and the Health Research Board (HRB) of Ireland.en
dc.format.extent27204-16en
dc.language.isoenen
dc.relation.ispartofseriesThe Journal of biological chemistry;
dc.relation.ispartofseries287;
dc.relation.ispartofseries32;
dc.rightsYen
dc.subjectImmunesuppressive cytokineen
dc.subjectGene regulationen
dc.subjectImmunologyen
dc.subjectIntegrinen
dc.subjectLymphocyteen
dc.subjectTransforming Growth Factor Beta (TGFbeta)en
dc.titleLeukocyte function-associated antigen-1/intercellular adhesion molecule-1 interaction induces a novel genetic signature resulting in T-cells refractory to transforming growth factor-β signaling.en
dc.typeJournal Articleen
dc.contributor.sponsorScience Foundation Ireland (SFI)en
dc.type.supercollectionscholarly_publicationsen
dc.type.supercollectionrefereed_publicationsen
dc.identifier.peoplefinderurlhttp://people.tcd.ie/longai
dc.identifier.peoplefinderurlhttp://people.tcd.ie/yvolkov
dc.identifier.peoplefinderurlhttp://people.tcd.ie/pfallon
dc.identifier.peoplefinderurlhttp://people.tcd.ie/kellehdp
dc.identifier.rssinternalid85302
dc.identifier.doihttp://dx.doi.org/10.1074/jbc.M112.376616
dc.rights.ecaccessrightsopenAccess
dc.subject.TCDThemeImmunology, Inflammation & Infectionen
dc.subject.TCDTagBiomedical sciencesen
dc.identifier.orcid_id0000-0002-9918-9960


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