T cell activation leads to protein kinase C theta-dependent inhibition of TGF-beta signaling

• Published in: The Journal of immunology (1950) 2010-08, Vol.185 (3), p.1568-1576
• Main Authors: Giroux, Martin, Delisle, Jean-Sébastien, O'Brien, Alan, Hébert, Marie-Josée, Perreault, Claude
• Format: Article
• Language: English
• Subjects: Animals; Antibodies, Monoclonal - physiology; CD28 Antigens - immunology; CD3 Complex - immunology; CD4-Positive T-Lymphocytes - enzymology; CD4-Positive T-Lymphocytes - immunology; CD4-Positive T-Lymphocytes - metabolism; Down-Regulation - genetics; Down-Regulation - immunology; Humans; Isoenzymes - genetics; Isoenzymes - physiology; Jurkat Cells; Lymphocyte Activation - immunology; Membrane Microdomains - drug effects; Membrane Microdomains - immunology; Membrane Microdomains - metabolism; Mice; Mice, Inbred C57BL; Mice, Transgenic; Phosphorylation - immunology; Protein Kinase C - genetics; Protein Kinase C - physiology; Protein Kinase C-theta; Receptors, Antigen, T-Cell - agonists; Receptors, Antigen, T-Cell - antagonists & inhibitors; Receptors, Antigen, T-Cell - physiology; Resting Phase, Cell Cycle - immunology; Signal Transduction - drug effects; Signal Transduction - immunology; Smad3 Protein - antagonists & inhibitors; Smad3 Protein - metabolism; Transforming Growth Factor beta1 - antagonists & inhibitors; Transforming Growth Factor beta1 - physiology
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.1000137

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.