When Toll-like receptor and T-cell receptor signals collide: A mechanism for enhanced CD8 T-cell effector function (136.11)

Abstract

Abstract Emerging reports reveal that activating toll-like receptor-2 (TLR)-MyD88 signals in CD8 T-lymphocytes enhances cytokine production and cytotoxicity. In the present study, we examined the physiological-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 and consequently augmented effector gene transcript and protein levels both in vivo and in vitro whereas, TLR2 agonist did not costimulate TLR2-/-OT-1 or MyD88-/-OT-1 T-cells. Elevated T-bet level in TLR2-MyD88-stimulated T-cells was a consequence of increased biosynthesis resulting from the enhanced activation of the mammalian target of rapamycin (mTOR) pathway. Inhibition of mTOR or blockade of phosphatidylinositol-3-kinase (PI3K)-Akt or PKC in T-cells abolished the costimulatory effects of the TLR2 agonist. In vivo, activating TLR2-MyD88 signals within OT-1 T-cells increased the levels of effector molecules 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 PKC signaling-dependent manner, highlighting a critical role for TLR-MyD88 signaling in T-cell activation and cytotoxicity. These findings offer the opportunity for improving the efficacy of vaccines and T-cell-based tumor-immunotherapies by manipulating TLR-MyD88 signaling within CD8 T-cells.