Leukocyte function-associated antigen-1/intercellular adhesion molecule-1 interaction induces a novel genetic signature resulting in T-cells refractory to transforming growth factor-ß signaling.
J Biol Chem
; 287(32): 27204-16, 2012 Aug 03.
Article
em En
| MEDLINE
| ID: mdl-22707713
ABSTRACT
The immunesuppressive cytokine TGF-ß 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-ß. 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-ß 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-ß 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-ß-mediated phosphorylation of SMAD2 and suppression of IL-2 secretion. Expression of SKI caused resistance to TGF-ß-mediated suppression of IL-2, but SMAD2 phosphorylation was unaffected. Blocking LFA-1 by neutralizing antibody or specific knockdown of TGF-ß inhibitory molecules by siRNA substantially restored LFA-1/ICAM-1-mediated alteration in TGF-ß signaling. LFA-1/ICAM-1-stimulated human and mouse T-cells were refractory to TGF-ß-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.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Linfócitos T
/
Transdução de Sinais
/
Antígeno-1 Associado à Função Linfocitária
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Fator de Crescimento Transformador beta
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Molécula 1 de Adesão Intercelular
Tipo de estudo:
Risk_factors_studies
Limite:
Humans
Idioma:
En
Ano de publicação:
2012
Tipo de documento:
Article