期刊
JOURNAL OF IMMUNOLOGY
卷 185, 期 3, 页码 1568-1576出版社
AMER ASSOC IMMUNOLOGISTS
DOI: 10.4049/jimmunol.1000137
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资金
- Fonds de la Recherche en Santedu Quebec (Groupe de recherche transdisciplinaire sur l'etude des predicteurs du rejet)
- Leukemia and Lymphoma Society of Canada
- Cole Foundation
- Canadian Institutes for Health Research
- Canadian Center of Excellence in Commercialization and Research
- Canada Foundation for Innovation
- Fonds de la Recherche en Santedu Quebec
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-beta Rs in lipid rafts together with inhibitory SMAD7. This effect is dependent on protein kinase C theta, a downstream TCR signaling intermediary, as revealed by both pharmacological inhibition and expression of dominant-negative and constitutively active protein kinase C theta 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. The Journal of Immunology, 2010, 185: 1568-1576.
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