Src kinases central to T-cell receptor signaling regulate TLR-activated innate immune responses from human T cells

Naveen Sharma, Ajay Suresh Akhade, Ayub Qadri

Research output: Contribution to journalArticlepeer-review

15 Scopus citations

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 languageEnglish (US)
Pages (from-to)238-244
Number of pages7
JournalInnate Immunity
Volume22
Issue number3
DOIs
StatePublished - Apr 1 2016
Externally publishedYes

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

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