When Toll-like receptor and T-cell receptor signals collide: a mechanism for enhanced CD8 T-cell effector function.
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 activation 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.
Geng
Degui
D
University of Maryland Greenebaum Cancer Center, 655 W. Baltimore Street, Baltimore, MD 21201, USA.
Zheng
Liqin
L
Srivastava
Ratika
R
Asprodites
Nicole
N
Velasco-Gonzalez
Cruz
C
Davila
Eduardo
E
D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000382:microbiology; D005786:Gene Expression Regulation; D053804:Granzymes / Q000276:immunology; D007371:Interferon-gamma / Q000235:genetics / Q000276:immunology; D051379:Mice; D053594:Myeloid Differentiation Factor 88 / Q000276:immunology; D054353:Perforin / Q000235:genetics / Q000276:immunology; D019869:Phosphatidylinositol 3-Kinases / Q000276:immunology; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000276:immunology; D011948:Receptors, Antigen, T-Cell / Q000276:immunology*; D020825:T-Box Domain Proteins / Q000235:genetics / Q000276:immunology; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000276:immunology; D051195:Toll-Like Receptor 2 / Q000276:immunology; D051193:Toll-Like Receptors / Q000276:immunology*; D000098815:T-bet Transcription Factor
D053804:Granzymes; D007371:Interferon-gamma; D053594:Myeloid Differentiation Factor 88; D054353:Perforin; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011493:Protein Kinase C; D011948:Receptors, Antigen, T-Cell; D020825:T-Box Domain Proteins; D058570:TOR Serine-Threonine Kinases; D051195:Toll-Like Receptor 2; D051193:Toll-Like Receptors; D000098815:T-bet Transcription Factor; C546843:mTOR protein, mouse