When Toll-like receptor and T-cell receptor signals collide: a mechanism for enhanced CD8 T-cell effector function
- 4 November 2010
- journal article
- Published by American Society of Hematology in Blood
- Vol. 116 (18), 3494-3504
- https://doi.org/10.1182/blood-2010-02-268169
Abstract
Emerging reports reveal that activating Toll-like receptor-2 (TLR2)–MyD88 signals in CD8 T lymphocytes enhances cytokine production and cytotoxicity; however, the signaling pathway remains undefined. In the present study, we examined the physiologic significance and molecular mechanisms involved in this process. We found that TLR2 engagement on T-cell receptor transgenic CD8 OT-1 T cells increased T-bet transcription factor levels consequently, augmenting effector transcript and protein levels both in vivo and in vitro. In contrast, TLR2 agonist did not costimulate TLR2−/−OT-1 or MyD88−/−OT-1 T cells. Elevated T-bet levels in TLR2-MyD88–activated T cells was a consequence of increased biosynthesis resulting from the enhanced acti- vation of the mammalian target of the rapamycin (mTOR) pathway. Inhibiting mTOR, Akt, or protein kinase C in T cells abolished the costimulatory effects of the TLR2 agonist. In vivo, activating TLR2–MyD88 signals in T cells increased effector-molecule levels and enhanced the clearance of Listeria monocytogenes-Ova. These results help define a signaling pathway linking the TLR-MyD88 and mTOR pathway in an Akt- and protein kinase C–dependent manner. These results highlight a critical role for MyD88 signaling in T-cell activation and cytotoxicity. Furthermore, these findings offer the opportunity for improving the efficacy of vaccines and T cell–based immunotherapies by targeting TLR-MyD88 signaling within T cells.Keywords
This publication has 46 references indexed in Scilit:
- The Adaptor Molecule MyD88 Directly Promotes CD8 T Cell Responses to Vaccinia VirusThe Journal of Immunology, 2009
- A critical role for direct TLR2-MyD88 signaling in CD8 T-cell clonal expansion and memory formation following vaccinia viral infectionBlood, 2009
- Engagement of Toll‐like receptor‐2 on cytotoxic T‐lymphocytes occursin vivoand augments antitumor activityThe FASEB Journal, 2008
- T cell expression of MyD88 is required for resistance toToxoplasma gondiiProceedings of the National Academy of Sciences of the United States of America, 2008
- TLR9 engagement on CD4 T lymphocytes represses γ-radiation–induced apoptosis through activation of checkpoint kinase response elementsBlood, 2008
- MyD88-mediated signals induce the bactericidal lectin RegIIIγ and protect mice against intestinal Listeria monocytogenes infectionThe Journal of Experimental Medicine, 2007
- The Adaptor Molecule MyD88 Activates PI-3 Kinase Signaling in CD4+ T Cells and Enables CpG Oligodeoxynucleotide-Mediated CostimulationImmunity, 2006
- Toll-like receptor control of the adaptive immune responsesNature Immunology, 2004
- Identification of specific gene expression profiles in human mast cells mediated by Toll-like receptor 4 and FcϵRIBlood, 2003
- PKC-θ is required for TCR-induced NF-κB activation in mature but not immature T lymphocytesNature, 2000