T cell activation leads to protein kinase C theta-dependent inhibition of TGF-beta signaling.
J Immunol
; 185(3): 1568-76, 2010 Aug 01.
Article
em En
| MEDLINE
| ID: mdl-20592275
ABSTRACT
TGF-beta is an ubiquitous cytokine that plays a pivotal role in the maintenance of self-tolerance and prevention of immunopathologies. Under steady-state conditions, TGF-beta keeps naive T cells in a resting state and inhibits Th1 and Th2 cell differentiation. Because rapid generation of Th1 and Th2 effector cells is needed in response to pathogen invasion, how do naive T cells escape from the quiescent state maintained by TGF-beta? We hypothesized that stimulation by strong TCR agonists might interfere with TGF-beta signaling. Using both primary mouse CD4(+) T cells and human Jurkat cells, we observed that strong TCR agonists swiftly suppress TGF-beta signaling. TCR engagement leads to a rapid increase in SMAD7 levels and decreased SMAD3 phosphorylation. We present evidence that TCR signaling hinders SMAD3 activation by inducing recruitment of TGF-betaRs in lipid rafts together with inhibitory SMAD7. This effect is dependent on protein kinase C, a downstream TCR signaling intermediary, as revealed by both pharmacological inhibition and expression of dominant-negative and constitutively active protein kinase C mutants. This work broadens our understanding of the cross-talk occurring between the TCR and TGF-beta signaling pathways and reveals that strong TCR agonists can release CD4 T cells from constitutive TGF-beta signaling. We propose that this process may be of vital importance upon confrontation with microbial pathogens.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Proteína Quinase C
/
Ativação Linfocitária
/
Linfócitos T CD4-Positivos
/
Transdução de Sinais
/
Fator de Crescimento Transformador beta1
/
Isoenzimas
Limite:
Animals
/
Humans
Idioma:
En
Revista:
J Immunol
Ano de publicação:
2010
Tipo de documento:
Article
País de afiliação:
Canadá