title: Prior TLR5 induction in human T cells results in a transient potentiation of subsequent TCR-induced cytokine production.
abstract: Activation of TLRs by components required for pathogen viability results in increased inflammation and an enhanced immune response to infection. Unlike their effects on other immune cells, TLR activation in the absence of T cell antigen receptor (TCR) induction has little effect on T cell activity. Instead, the simultaneous induction of TLR and TCR results in increased cytokine release compared to TCR treatment alone. Thus, the current model states that TLRs alter T cell function only if activated at the same time as the TCR. In this study, we tested the novel hypothesis that prior TLR induction can also alter TCR-mediated functions. We found that human T cells responded to ligands for TLR2 and TLR5. However, only prior TLR5 induction potentiated subsequent TCR-mediated cytokine production in human T cells. This response required at least 24h of TLR5 induction and lasted for approximately 24-36h after removal of a TLR5 ligand. Interestingly, prior TLR5 induction enhanced TCR-mediated activation of Akt without increasing Lck, LAT or ERK kinase phosphorylation. Together, our studies show that TLR5 induction leads to a transient increase in the sensitivity of T cells to TCR stimulation by selectively enhancing TCR-mediated Akt function, highlighting that timeframe when TLR5 can potentiate TCR-induced downstream functions are significantly longer that previously appreciated.
authors.affiliation: Department of Microbiology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, United States.
authors.forename: Mikaela M
authors.initials: MM
authors.lastname: Tremblay
authors.forename: Mahmood Y
authors.initials: MY
authors.lastname: Bilal
authors.forename: Jon C D
authors.initials: JC
authors.lastname: Houtman
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D002460:Cell Line; D016207:Cytokines / Q000096:biosynthesis*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005408:Flagellin / Q000276:immunology; D006801:Humans; D053592:Interleukin-1 Receptor-Associated Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D008213:Lymphocyte Activation / Q000276:immunology*; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000276:immunology*; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D051195:Toll-Like Receptor 2 / Q000378:metabolism; D051198:Toll-Like Receptor 5 / Q000096:biosynthesis / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D016207:Cytokines; C110810:LAT protein, human; D008565:Membrane Proteins; D011948:Receptors, Antigen, T-Cell; C495342:TLR2 protein, human; C495346:TLR5 protein, human; D051195:Toll-Like Receptor 2; D051198:Toll-Like Receptor 5; D005408:Flagellin; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck); D053592:Interleukin-1 Receptor-Associated Kinases; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases
keywords: APBTs; APC; IFN-γ; PAM; PAM3CSK4; Signal transduction; T cell receptor; T cells; Toll-like receptor 5; activated peripheral blood T cells; antigen presenting cells; interferon-γ