| First Author | Giroux M | Year | 2010 |
| Journal | J Immunol | Volume | 185 |
| Issue | 3 | Pages | 1568-76 |
| PubMed ID | 20592275 | Mgi Jnum | J:162461 |
| Mgi Id | MGI:4819024 | Doi | 10.4049/jimmunol.1000137 |
| Citation | Giroux M, et al. (2010) T cell activation leads to protein kinase Ctheta-dependent inhibition of TGF-beta signaling. J Immunol 185(3):1568-76 |
| abstractText | 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. |
