T cell activation leads to protein kinase C theta-dependent inhibition of TGF-beta signaling.
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.
Giroux
Martin
M
Institute for Research in Immunology and Cancer, Montreal, Quebec H3C 3J7, Canada.
Delisle
Jean-Sébastien
JS
O'Brien
Alan
A
Hébert
Marie-Josée
MJ
Perreault
Claude
C
D000818:Animals; D000911:Antibodies, Monoclonal / Q000502:physiology; D018106:CD28 Antigens / Q000276:immunology; D017252:CD3 Complex / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000201:enzymology / Q000276:immunology* / Q000378:metabolism; D015536:Down-Regulation / Q000235:genetics / Q000276:immunology; D006801:Humans; D007527:Isoenzymes / Q000235:genetics / Q000502:physiology*; D019169:Jurkat Cells; D008213:Lymphocyte Activation / Q000276:immunology*; D021962:Membrane Microdomains / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010766:Phosphorylation / Q000276:immunology; D011493:Protein Kinase C / Q000235:genetics / Q000502:physiology*; D000074121:Protein Kinase C-theta; D011948:Receptors, Antigen, T-Cell / Q000819:agonists / Q000037:antagonists & inhibitors / Q000502:physiology; D016192:Resting Phase, Cell Cycle / Q000276:immunology; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology*; D051900:Smad3 Protein / Q000037:antagonists & inhibitors / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000037:antagonists & inhibitors* / Q000502:physiology*
D000911:Antibodies, Monoclonal; D018106:CD28 Antigens; D017252:CD3 Complex; D007527:Isoenzymes; D011948:Receptors, Antigen, T-Cell; D051900:Smad3 Protein; D053773:Transforming Growth Factor beta1; C489593:Prkcq protein, mouse; D011493:Protein Kinase C; D000074121:Protein Kinase C-theta