Src kinases central to T-cell receptor signaling regulate TLR-activated innate immune responses from human T cells.
TLRs have a fundamental role in immunity. We have recently reported that stimulation of TLR2 and TLR5 in freshly isolated and activated human T cells with microbial ligands without concomitant activation through the TCR brings about secretion of neutrophil chemoattractant, CXCL8, and effector cytokine, IFN-γ, respectively. However, the mechanism of TLR signaling in T cells has not been worked out. Here, we show that the Src family kinases, p56(lck)(Lck) and p59(fyn)(Fyn), which are essential for activation of T cells through the TCR, are also critical for signal transduction through TLRs in human T cells. The secretion of CXCL8 following stimulation of the model human T cell line, Jurkat, with the TLR5 ligand, flagellin, was reduced in presence of the Src-kinase inhibitor, PP2 and specific inhibitors of Lck and Fyn. These inhibitors suppressed generation of activated JNK and p38, which were both required for TLR-induced CXCL8 production. The Lck-deficient derivative of Jurkat, JCam1.6, responded poorly to TLR2, TLR5 and TLR7 agonists, and did not generate active signaling intermediates. Lck and Fyn inhibitors also reduced TLR5-induced IFN-γ secretion from the activated T cell phenotype-representing T cell line, HuT78, without modulating JNK and p38 activation. These results reveal that TCR and TLRs share key proximal signaling regulators in T cells.
['Sharma|Naveen|N|', 'Akhade|Ajay Suresh|AS|', 'Qadri|Ayub|A|']
D005408:Flagellin D006801:Humans D007113:Immunity, Innate D007371:Interferon-gamma D016209:Interleukin-8 D019169:Jurkat Cells D008213:Lymphocyte Activation D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck) D009154:Mutation D051076:Proto-Oncogene Proteins c-fyn D011743:Pyrimidines D011948:Receptors, Antigen, T-Cell D015398:Signal Transduction D013601:T-Lymphocytes D051195:Toll-Like Receptor 2 D051198:Toll-Like Receptor 5 D051199:Toll-Like Receptor 7 D048051:p38 Mitogen-Activated Protein Kinases
Src kinases T-cell receptor innate immune response human T cells Toll-like receptor