dc.contributor.author | Volkov, Yuri | |
dc.contributor.author | Kelleher, Dermot | |
dc.contributor.author | Long, Aideen | |
dc.contributor.author | Fallon, Padraic | |
dc.contributor.author | Verma, Navin K. | |
dc.contributor.author | Dempsey, Eugene | |
dc.contributor.author | Davies, Anthony | |
dc.contributor.author | Barry, Sean P. | |
dc.date.accessioned | 2019-11-21T10:47:27Z | |
dc.date.available | 2019-11-21T10:47:27Z | |
dc.date.issued | 2012 | |
dc.date.submitted | 2012 | en |
dc.identifier.citation | Verma, 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, 32 | en |
dc.identifier.other | Y | |
dc.identifier.uri | http://www.jbc.org/content/287/32/27204 | |
dc.identifier.uri | http://hdl.handle.net/2262/90814 | |
dc.description.abstract | The 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.sponsorship | This 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.extent | 27204-16 | en |
dc.language.iso | en | en |
dc.relation.ispartofseries | The Journal of biological chemistry; | |
dc.relation.ispartofseries | 287; | |
dc.relation.ispartofseries | 32; | |
dc.rights | Y | en |
dc.subject | Immunesuppressive cytokine | en |
dc.subject | Gene regulation | en |
dc.subject | Immunology | en |
dc.subject | Integrin | en |
dc.subject | Lymphocyte | en |
dc.subject | Transforming Growth Factor Beta (TGFbeta) | en |
dc.title | 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. | en |
dc.type | Journal Article | en |
dc.type.supercollection | scholarly_publications | en |
dc.type.supercollection | refereed_publications | en |
dc.identifier.peoplefinderurl | http://people.tcd.ie/longai | |
dc.identifier.peoplefinderurl | http://people.tcd.ie/yvolkov | |
dc.identifier.peoplefinderurl | http://people.tcd.ie/pfallon | |
dc.identifier.peoplefinderurl | http://people.tcd.ie/kellehdp | |
dc.identifier.rssinternalid | 85302 | |
dc.identifier.doi | http://dx.doi.org/10.1074/jbc.M112.376616 | |
dc.rights.ecaccessrights | openAccess | |
dc.subject.TCDTheme | Immunology, Inflammation & Infection | en |
dc.subject.TCDTag | Biomedical sciences | en |
dc.identifier.orcid_id | 0000-0002-9918-9960 | |
dc.contributor.sponsor | Science Foundation Ireland (SFI) | en |