T Cell Activation Leads to Protein Kinase Cθ-Dependent Inhibition of TGF-β Signaling

Abstract

TGF-β is an ubiquitous cytokine that plays a pivotal role in the maintenance of self-tolerance and prevention of immunopathologies. Under steady-state conditions, TGF-β 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-β? We hypothesized that stimulation by strong TCR agonists might interfere with TGF-β signaling. Using both primary mouse CD4+ T cells and human Jurkat cells, we observed that strong TCR agonists swiftly suppress TGF-β 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-βRs in lipid rafts together with inhibitory SMAD7. This effect is dependent on protein kinase Cθ, a downstream TCR signaling intermediary, as revealed by both pharmacological inhibition and expression of dominant-negative and constitutively active protein kinase Cθ mutants. This work broadens our understanding of the cross-talk occurring between the TCR and TGF-β signaling pathways and reveals that strong TCR agonists can release CD4 T cells from constitutive TGF-β signaling. We propose that this process may be of vital importance upon confrontation with microbial pathogens.