Abstract
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, p56lck (Lck) and p59fyn (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.
Original language | English (US) |
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Pages (from-to) | 238-244 |
Number of pages | 7 |
Journal | Innate Immunity |
Volume | 22 |
Issue number | 3 |
DOIs | |
State | Published - Apr 1 2016 |
Externally published | Yes |
Keywords
- Src kinases
- T-cell receptor
- Toll-like receptor
- human T cells
- innate immune response
ASJC Scopus subject areas
- Microbiology
- Immunology
- Molecular Biology
- Cell Biology
- Infectious Diseases