title: Src kinases central to T-cell receptor signaling regulate TLR-activated innate immune responses from human T cells.
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, 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.
authors.affiliation: Hybridoma Laboratory, National Institute of Immunology, Aruna Asaf Ali Marg, New Delhi 110067, India.
authors.forename: Naveen
authors.initials: N
authors.lastname: Sharma
authors.affiliation: Hybridoma Laboratory, National Institute of Immunology, Aruna Asaf Ali Marg, New Delhi 110067, India.
authors.forename: Ajay Suresh
authors.initials: AS
authors.lastname: Akhade
authors.affiliation: Hybridoma Laboratory, National Institute of Immunology, Aruna Asaf Ali Marg, New Delhi 110067, India ayub@nii.ac.in.
authors.forename: Ayub
authors.initials: A
authors.lastname: Qadri
mesh_terms: D005408:Flagellin / Q000276:immunology; D006801:Humans; D007113:Immunity, Innate; D007371:Interferon-gamma / Q000378:metabolism; D016209:Interleukin-8 / Q000378:metabolism; D019169:Jurkat Cells; D008213:Lymphocyte Activation / Q000187:drug effects / Q000235:genetics; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / Q000235:genetics / Q000378:metabolism*; D009154:Mutation / Q000235:genetics; D051076:Proto-Oncogene Proteins c-fyn / Q000378:metabolism*; D011743:Pyrimidines / Q000494:pharmacology; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D013601:T-Lymphocytes / Q000187:drug effects / Q000382:microbiology / Q000502:physiology*; D051195:Toll-Like Receptor 2 / Q000378:metabolism; D051198:Toll-Like Receptor 5 / Q000378:metabolism*; D051199:Toll-Like Receptor 7 / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: C412373:AG 1879; D016209:Interleukin-8; D011743:Pyrimidines; D011948:Receptors, Antigen, T-Cell; C495342:TLR2 protein, human; C495346:TLR5 protein, human; C495348:TLR7 protein, human; D051195:Toll-Like Receptor 2; D051198:Toll-Like Receptor 5; D051199:Toll-Like Receptor 7; D005408:Flagellin; D007371:Interferon-gamma; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck); D051076:Proto-Oncogene Proteins c-fyn; D048051:p38 Mitogen-Activated Protein Kinases
keywords: Src kinases; T-cell receptor; Toll-like receptor; human T cells; innate immune response